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Aim: To compare the impact of four surgical procedures (mini‐gastric bypass, sleeve gastrectomy, ileal transposition and transit bipartition) vs medical management on gut peptide secretion, β‐cell function and resolution of hyperglycaemia in people with type 2 diabetes. Research design and methods: A mixed‐meal tolerance test was administered 6–24 months after each surgical procedure (mini‐gastric bypass, sleeve gastrectomy, ileal transposition and transit bipartition; n=30 in each group) and the results were compared with those obtained in matched lean (n=30) and obese (n=30) people with type 2 diabetes undergoing medical management. Results: Participants in the mini‐gastric bypass and ileal transposition groups had a greater increase in plasma glucose concentration after the mixed‐meal tolerance test than those in the sleeve gastrectomy and transit bipartition groups. Participants in the mini‐gastric bypass group exhibited the greatest increase in the incremental area under the curve of plasma glucose concentration above baseline (P<0.0001). Insulin sensitivity was similar across surgical groups, and statistically greater in participants in the surgical groups than in obese participants in the non‐surgical group (P<0.0001). β‐cell responsiveness to glucose was greater in participants in the sleeve gastrectomy and transit bipartition groups than in the mini‐gastric bypass and ileal transposition groups (P<0.001) despite a smaller incremental increase above baseline in the area under the plasma glucagon‐like peptide‐1 concentration curve relative to ileal transposition. Postoperative β‐cell function was the strongest predictor of hyperglycaemia resolution. Conclusions: The present study showed that the level of β‐cell function after bariatric surgery is the strongest predictor of hyperglycaemia resolution. The study also demonstrates a disconnect between postprandial GLP‐1 levels and β‐cell function among the studied surgical procedures. What's new?: The effects of four different surgical procedures (one‐anastomosis mini‐gastric bypass, sleeve gastrectomy, ileal transposition and transit bipartition])were compared with those of medical management on gut peptide secretion, β‐cell function and resolution of hyperglycaemia in participants with type 2 diabetes mellitus.The level of β‐cell function after bariatric surgery was the strongest predictor of hyperglycaemia resolution.There is a disconnect between postprandial glucagon‐like peptide‐1 levels and β‐cell function between the studied surgical procedures. [ABSTRACT FROM AUTHOR]

The article discusses a case of non-Langerhans cell histiocytosis in a 35-year-old man with acute myelogenous leukemia relapse. The patient presented with violaceous infiltrated papules over the arms, and biopsy confirmed the diagnosis of non-LCH. The article explores the relationship between histiocytosis and myeloid neoplasms, suggesting a common clonal origin and implications for therapy based on genetic mutations. The case highlights the unique development of non-LCH in a patient with AML and emphasizes the potential paraneoplastic syndrome associated with histiocytic disorders in patients with myeloproliferative diseases. [Extracted from the article]

The recently completed EMPA-REG study showed that empagliflozin significantly decreased the major adverse cardiac events ( MACE) endpoint, which comprised cardiovascular death, non-fatal myocardial infarction ( MI) and stroke, in patients with high-risk type 2 diabetes ( T2DM), primarily through a reduction in cardiovascular death, without a significant decrease in either MI or stroke. In the PROactive study, pioglitazone decreased the MACE endpoint by a similar degree to that observed in the EMPA-REG study, through a marked reduction in both recurrent MI and stroke and a modest reduction in cardiovascular death. These observations suggest that pioglitazone might be an ideal agent to combine with empagliflozin to further reduce cardiovascular events in patients with high-risk diabetes as empagliflozin also promotes salt/water loss and would be expected to offset any fluid retention associated with pioglitazone therapy. In the present paper, we provide an overview of the potential benefits of combined pioglitazone/empagliflozin therapy to prevent cardiovascular events in patients with T2DM. [ABSTRACT FROM AUTHOR]

Aim To test our hypothesis that initiating therapy with a combination of agents known to improve insulin secretion and insulin sensitivity in subjects with new-onset diabetes would produce greater, more durable reduction in glycated haemoglobin ( HbA1c) levels, while avoiding hypoglycaemia and weight gain, compared with sequential addition of agents that lower plasma glucose but do not correct established pathophysiological abnormalities. Methods Drug-naïve, recently diagnosed subjects with type 2 diabetes mellitus ( T2DM) were randomized in an open-fashion design in a single-centre study to metformin/pioglitazone/exenatide (triple therapy; n = 106) or an escalating dose of metformin followed by sequential addition of sulfonylurea and glargine insulin (conventional therapy; n = 115) to maintain HbA1c levels at <6.5% for 2 years. Results Participants receiving triple therapy experienced a significantly greater reduction in HbA1c level than those receiving conventional therapy (5.95 vs. 6.50%; p < 0.001). Despite lower HbA1c values, participants receiving triple therapy experienced a 7.5-fold lower rate of hypoglycaemia compared with participants receiving conventional therapy. Participants receiving triple therapy experienced a mean weight loss of 1.2 kg versus a mean weight gain of 4.1 kg (p < 0.01) in those receiving conventional therapy. Conclusion The results of this exploratory study show that combination therapy with metformin/pioglitazone/exenatide in patients with newly diagnosed T2DM is more effective and results in fewer hypoglycaemic events than sequential add-on therapy with metformin, sulfonylurea and then basal insulin. [ABSTRACT FROM AUTHOR]

Maintaining normoglycaemia not only reduces the risk of diabetic microvascular complications but also corrects the metabolic abnormalities that contribute to the development and progression of hyperglycaemia, that is insulin resistance and beta-cell dysfunction. Progressive beta-cell failure, in addition to side effects associated with many current antidiabetic agents, for example hypoglycaemia and weight gain, presents major obstacles to the achievement of the recommended goal of glycaemic control in patients with type 2 diabetes mellitus (T2DM). Thus, novel effective therapies are needed for optimal glucose control in subjects with T2DM. Most recently, specific inhibitors of the renal sodium-glucose cotransporter 2 (SGLT2) have been developed to produce glucosuria and lower the plasma glucose concentration. Because of the iR unique mechanism of action, which is independent of insulin secretion and insulin action, these agents are effective in lowering the plasma glucose concentration in all stages of the disease and can be combined with all other antidiabetic agents. In this review, we will summarize the available data concerning the mechanism of action, efficacy and safety of this novel class of antidiabetic agents. [ABSTRACT FROM AUTHOR]

Objective To examine the association between insulin resistance in skeletal muscle and liver in non-diabetic subjects. Research design and methods A total of 182 Mexican American subjects without Type 2 diabetes underwent an oral glucose tolerance test and euglycaemic–hyperinsulinaemic clamp performed with 3[H]glucose. Insulin sensitivity in skeletal muscle was measured as the insulin-stimulated rate of total glucose disposal during the insulin clamp divided by steady-state plasma insulin concentration (TGD/SSPI). Hepatic insulin resistance was measured as the product of basal hepatic glucose production and fasting plasma insulin concentration (HGP × FPI). Results Hepatic insulin resistance was strongly correlated ( r = 0.68, P < 0.0001) with skeletal muscle insulin resistance. Thirty-eight per cent of subjects had increased insulin resistance in both liver and skeletal muscle, while 39% were insulin sensitive in both skeletal muscle and liver. Twenty-three per cent of subjects were discordant for muscle and hepatic insulin resistance ( P < 0.0001). Subjects with increased skeletal muscle insulin resistance had a higher 2-h plasma glucose concentration, greater incremental area under the plasma glucose concentration curve, lower fasting plasma insulin concentration and lower rate of basal hepatic glucose production compared with subjects with increased insulin resistance in liver. Conclusion In non-diabetic subjects, insulin resistance in skeletal muscle is an important determinant of the fasting and 2-h plasma glucose concentrations and strongly correlates with hepatic insulin resistance. [ABSTRACT FROM AUTHOR]

Aim: To examine the renal effects of sodium-glucose cotransporter-2 (SGLT2) inhibition among non-diabetic individuals with chronic kidney disease (CKD) in a real-world setting., Methods: We collected de-identified data on adults without diabetes and with an estimated glomerular filtration rate (eGFR) of 25-60 mL/min/1.73 m 2 , who initiated the SGLT2 inhibitors dapagliflozin or empagliflozin between September 2020 and November 2022 at Maccabi Healthcare Services, an Israeli health maintenance organization. We assessed the effects of SGLT2 inhibitors on renal function (changes in eGFR slope/time). Index date was defined as the date of the first dispensing of SGLT2 inhibitors. Annual baseline slope was calculated using all eGFR measurements during the 2 years prior to index date (median = 7 measurements), while annual follow-up slope was calculated from all evaluations during 90-900 days post index date, along with baseline measurement at index date (median = 6 measurements). Paired t tests were used to compare differences between baseline and follow-up annual slopes., Results: Of a total of 354 participants with CKD, without diabetes, who received SGLT2 inhibitors and were followed for a median of 527 days, the mean age was 72.8 ± 11.8 years, 26% were female, and 91% used renin-angiotensin system blockade. The mean eGFR was 45.4 ± 9.5 mL/min/1.73 m 2 . The mean body mass index was 29.1 ± 5.4 kg/m 2 . During the year before index date, 146 participants (41%) had a urinary albumin to creatinine ratio (UACR) <30 mg/g, 81 (23%) had a UACR of 30-300 mg/g, 74 (21%) had a UACR >300 mg/g, and 53 (15%) had no UACR evaluation. The mean eGFR slope over time was -5.6 ± 7.7 mL/min/1.73 m 2 per year at baseline, which improved to -1.7 ± 6.8 mL/min/1.73 m 2 per year after SGLT2 inhibitor administration (p <0.001). This effect was independent of UACR., Conclusion: In a real-world study of primarily older non-diabetic adults with CKD, SGLT2 inhibition was associated with a slower rate of kidney function decline, regardless of baseline UACR level., (© 2024 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aim: To examine the impact of increased hepatic glucose production (HGP) on the decrease in plasma glucose concentration caused by empagliflozin in individuals living with diabetes and in nondiabetic individuals., Methods: A total of 36 individuals living with diabetes and 34 nondiabetic individuals were randomized to receive, in double-blind fashion, empagliflozin or matching placebo in a 2:1 treatment ratio. Following an overnight fast, HGP was measured with 3- 3 H-glucose infusion before, at the start of, and 3 months after therapy with empagliflozin., Results: On Day 1 of empagliflozin administration, the increase in urinary glucose excretion (UGE) in individuals with normal glucose tolerance was smaller than in those with impaired glucose tolerance and those living with diabetes, and was accompanied by an increase in HGP in all three groups. The amount of glucose returned to the systemic circulation as a result of the increase in HGP was smaller than that excreted by the kidney during the first 3 h after empagliflozin administration, resulting in a decrease in fasting plasma glucose (FPG) concentration. After 3 h, the increase in HGP was in excess of UGE, leading to a small increase in plasma glucose concentration, which reached a new steady state. After 12 weeks, the amount of glucose returned to the circulation due to the empagliflozin-induced increase in HGP was comparable with that excreted by the kidney in all three groups., Conclusion: The balance between UGE and increase in HGP immediately after sodium-glucose cotransporter-2 (SGLT2) inhibition determined the magnitude of decrease in FPG and the new steady state which was achieved. After 12 weeks, the increase in HGP caused by empagliflozin closely matched the amount of glucose excreted by the kidneys; thus, FPG level remained stable despite the continuous urinary excretion of glucose caused by SGLT2 inhibition., (© 2023 John Wiley & Sons Ltd.)

Background: 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., Methods: 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., Results: 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., Conclusions: 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., (© 2023 John Wiley & Sons Ltd.)

Aims: To examine the effect of pioglitazone on epicardial (EAT) and paracardial adipose tissue (PAT) and measures of diastolic function and insulin sensitivity in patients with type 2 diabetes mellitus (T2DM)., Methods: Twelve patients with T2DM without clinically manifest cardiovascular disease and 12 subjects with normal glucose tolerance (NGT) underwent cardiac magnetic resonance imaging to quantitate EAT and PAT and diastolic function before and after pioglitazone treatment for 24 weeks. Whole-body insulin sensitivity was measured with a euglycaemic insulin clamp and the Matsuda Index (oral glucose tolerance test)., Results: Pioglitazone reduced glycated haemoglobin by 0.9% (P < 0.05), increased HDL cholesterol by 7% (P < 0.05), reduced triacylglycerol by 42% (P < 0.01) and increased whole-body insulin-stimulated glucose uptake by 71% (P < 0.01) and Matsuda Index by 100% (P < 0.01). In patients with T2DM, EAT (P < 0.01) and PAT (P < 0.01) areas were greater compared with subjects with NGT, and decreased by 9% (P = 0.03) and 9% (P = 0.09), respectively, after pioglitazone treatment. Transmitral E/A flow rate and peak left ventricular flow rate (PLVFR) were reduced in T2DM versus NGT (P < 0.01) and increased following pioglitazone treatment (P < 0.01-0.05). At baseline normalized PLVFR inversely correlated with EAT (r = -0.45, P = 0.03) but not PAT (r = -0.29, P = 0.16). E/A was significantly and inversely correlated with EAT (r = -0.55, P = 0.006) and PAT (r = -0.40, P = 0.05). EAT and PAT were inversely correlated with whole-body insulin-stimulated glucose uptake (r = -0.68, P < 0.001) and with Matsuda Index (r = 0.99, P < 0.002)., Conclusion: Pioglitazone reduced EAT and PAT areas and improved left ventricular (LV) diastolic function in T2DM. EAT and PAT are inversely correlated (PAT less strongly) with LV diastolic function and both EAT and PAT are inversely correlated with measures of insulin sensitivity., (© 2022 John Wiley & Sons Ltd.)

Aim: To examine the efficacy of glucose-lowering medications in subgroups of patients with type 2 diabetes mellitus (T2DM)., Research Design and Methods: Cluster analysis was performed in participants in the Efficacy and Durability of Initial Combination Therapy for Type 2 Diabetes (EDICT) study and the Qatar study using age, body mass index (BMI), glycated haemoglobin (HbA1c), and homeostatic model assessment of insulin resistance (HOMA-IR) and beta-cell function (HOMA-β). Participants also underwent an oral glucose tolerance test with measurement of plasma glucose, insulin and C-peptide concentrations to derive independent measures of insulin secretion and insulin sensitivity. The response to glucose-lowering therapies (change in HbA1c) was measured in each participant cluster for 3 years., Results: Three distinct and comparable clusters/groups of T2DM patients were identified in both the EDICT and Qatar studies. Participants in Group 1 had the highest HbA1c and manifested severe insulin deficiency. Participants in Group 3 had comparable insulin sensitivity to those in Group 1 but better beta-cell function and better glucose control. Participants in Group 2 had the highest BMI with severe insulin resistance accompanied by marked hyperinsulinaemia, which was primarily attributable to decreased insulin clearance. Unexpectedly, participants in Group 1 had better response to combination therapy with pioglitazone plus exenatide than with insulin therapy or metformin sequentially followed by glipizide and basal insulin, while participants in Group 2 responded equally well to both therapies despite very severe insulin resistance., Conclusion: Distinct metabolic phenotypes characterize different T2DM clusters and differential responses to glucose-lowering therapies. Participants with severe insulin deficiency respond better to agents that preserve beta-cell function, while, surprisingly, patients with severe insulin resistance did not respond favourably to insulin sensitizers., (© 2022 John Wiley & Sons Ltd.)

Aims: Pioglitazone is a potent insulin-sensitizing drug with anti-atherosclerotic properties, but adverse effects have limited its use. We assessed the benefits and risks of lower versus higher doses of pioglitazone taken by participants in the Insulin Resistance Intervention in Stroke Trial., Materials and Methods: Efficacy [myocardial infarction (MI) or recurrent stroke] new-onset diabetes) and adverse outcomes (oedema, weight gain, heart failure and bone fracture) were examined for subjects assigned to pioglitazone or placebo within strata defined by mode dose of study drug taken (i.e. the dose taken on most days in the study)., Results: Among the 1938 patients randomized to pioglitazone, the mode dose was <15 mg/day in 546 participants, 15 mg/day in 128, 30 mg/day in 89, and 45 mg/day in 1175. There was no significant effect on stroke/MI or new-onset diabetes with <15 mg/day. For 15 mg/30 mg/day pooled, the adjusted hazard ratios (95% CI) for stroke/MI were 0.48 (0.30, 0.76; p = .002) and 0.74 (0.69, 0.94) for 45 mg/day. For new-onset diabetes, the adjusted hazard ratios were 0.34 (0.15, 0.81; p = .001) and 0.31 (0.59, 0.94; p = .001) respectively. For oedema, weight gain and heart failure, the risk estimates for pioglitazone were lower for subjects taking <45 mg daily. For fractures, the increased risk with pioglitazone was similar across all dose strata., Conclusions: Lower doses of pioglitazone appear to confer much of the benefit with less adverse effects than the full dose. Further study is needed to confirm these findings so that clinicians may optimize dosing of this secondary prevention strategy in patients with stroke., (© 2022 John Wiley & Sons Ltd.)

Aim: To compare the efficacy of triple therapy (metformin/exenatide/pioglitazone) versus stepwise conventional therapy (metformin → glipizide → glargine insulin) on liver fat content and hepatic fibrosis in newly diagnosed, drug-naïve patients with type 2 diabetes., Methods: Sixty-eight patients completed the 6-year follow-up and had an end-of-study (EOS) FibroScan to provide measures of steatosis (controlled attenuation parameter [CAP] in dB/m) and fibrosis (liver stiffness measurement [LSM] in kPa); 59 had magnetic resonance imaging-proton density fat fraction (MRI-PDFF) to measure liver fat., Results: At EOS, HbA1c was 6.8% and 6.0% in triple and conventional therapy groups, respectively (P = .0006). Twenty-seven of 39 subjects (69%) receiving conventional therapy had grade 2/3 steatosis (CAP, FibroScan) versus nine of 29 (31%) in triple therapy (P = .0003). Ten of 39 (26%) subjects receiving conventional therapy had stage 3/4 fibrosis (LSM) versus two of 29 (7%) in triple therapy (P = .04). Conventional therapy subjects had more liver fat (MRI-PDFF) than triple therapy (12.9% vs. 8.8%, P = .03). The severity of steatosis (CAP) (r = 0.42, P < .001) and fibrosis (LSM) (r = -0.48, P < .001) correlated inversely with the Matsuda Index of insulin sensitivity, but not with percentage body fat. Aspartate aminotransferase (AST) to Platelet Ratio Index (APRI), non-alcoholic fatty liver disease fibrosis score (NFS), plasma AST, and alanine aminotransferase (ALT) all decreased significantly with triple therapy, but only the decrease in plasma AST and ALT correlated with the severity of steatosis and fibrosis at EOS., Conclusions: At EOS, subjects with type 2 diabetes treated with triple therapy had less hepatic steatosis and fibrosis versus conventional therapy; the severity of hepatic steatosis and fibrosis were both strongly and inversely correlated with insulin resistance; and changes in liver fibrosis scores (APRI, NFS, Fibrosis-4, and AST/ALT ratio) have limited value in predicting response to therapy., (© 2022 John Wiley & Sons Ltd.)

Aim: To identify predictors of response to glucose-lowering therapy in patients with new-onset diabetes and very high HbA1c (>10%)., Methods: The study included EDICT participants with an initial HbA1c of more than 10% (N = 104). All subjects received a 75-g oral glucose tolerance test (OGTT) before initiation of therapy, and then were randomized to receive: (a) initial triple therapy with metformin, pioglitazone and exenatide versus (b) stepwise conventional therapy with metformin followed by glipizide and then glargine insulin to reduce HbA1c to less than 6.5%. Insulin secretion and insulin resistance were calculated with OGTT-derived indices., Results: Sixty-one per cent of participants in the conventional therapy group achieved HbA1c of less than 6.5% at 6 months without need of insulin therapy compared with 78% in the triple therapy group (P = NS). Insulin secretion at baseline was the strongest predictor of subjects who did not require insulin therapy; a cut point of CPEP 120 /CPEP 0 -the ratio between plasma C-peptide concentration at 120 minutes during the OGTT and fasting plasma C-peptide concentration-of more than 1.7 predicted subjects who achieved the treatment target without insulin, irrespective of the fasting plasma glucose (FPG) concentration and whether or not they were started on conventional or triple therapy. Subjects with a CPEP 120 /CPEP 0 of less than 1.7 plus FPG of 269 mg/dL or less (≤14.9 mmoL/L) also achieved the treatment goal with triple therapy., Conclusion: Insulin secretion in response to a 75-g OGTT predicts the need for insulin therapy at the time of type 2 diabetes (T2D) diagnosis. A cut point of 1.7 of CPEP 120 /CPEP 0 provides a useful clinical tool to individualize glucose-lowering therapy in patients with new-onset T2D and HbA1c of more than 10%., (© 2021 John Wiley & Sons Ltd.)

Aim: To examine the long-term efficacy of thiazolidinedione plus a glucagon-like peptide-1 receptor agonist versus basal-bolus insulin on glycaemic control and beta-cell function in patients with poorly controlled type 2 diabetes (T2D) on metformin plus sulphonylurea., Materials and Methods: Three hundred and thirty-one patients with poorly controlled T2D were recruited over 3 years and were followed for an additional year. Subjects received a 75 g oral glucose tolerance test (OGTT) at baseline and at study end. After completing the baseline OGTT, subjects were randomized to receive either pioglitazone plus weekly exenatide (combination therapy) or basal/bolus insulin (insulin therapy) to maintain an HbA1c of less than 7.0%. The primary outcome of the study was the difference in HbA1c at study end between the two treatment groups., Results: Both therapies caused a robust decrease in HbA1c. However, combination therapy caused a greater decrement (-1.1%, P < .0001) than insulin therapy, and more subjects in the combination therapy group (86%) achieved the American Diabetes Association goal of glycaemic control (HbA1c < 7.0%) than those in the insulin therapy group (44%) (P < .0001). Both therapies improved insulin secretion. However, the improvement in insulin secretion with combination therapy was 2.5-fold greater (P < .001) than with insulin therapy (50%). Insulin therapy caused more weight gain and hypoglycaemia., Conclusion: Both combination therapy and insulin therapy effectively reduced HbA1c in poorly controlled T2D on multiple oral agents. However, combination therapy produced a greater improvement in insulin secretion and decrease in HbA1c with a lower risk of hypoglycaemia., (© 2020 John Wiley & Sons Ltd.)

Background: Increasing evidence suggests that metabolism affects brain physiology. Here, we examine the effect of GLP-1 on simple visual-evoked functional Magnetic Resonance Imaging (fMRI) responses in cortical areas., Methods: Lean (n = 10) and nondiabetic obese (n = 10) subjects received exenatide (a GLP-1 agonist) or saline infusion, and fMRI responses to visual stimuli (food and nonfood images) were recorded. We analysed the effect of exenatide on fMRI signals across the cortical surface with special reference to the visual areas. We evaluated the effects of exenatide on the raw fMRI signal and on the fMRI signal change during visual stimulation (vs rest)., Results: In line with previous studies, we find that exenatide eliminates the preference for food (over nonfood) images present under saline infusion in high-level visual cortex (temporal pole). In addition, we find that exenatide (vs saline) also modulates the response of early visual areas, enhancing responses to both food and nonfood images in several extrastriate occipital areas, similarly in obese and lean participants. Unexpectedly, exenatide increased fMRI raw signals (signal intensity during rest periods without stimulation) in a large occipital region, which were negatively correlated to BMI., Conclusions: In both lean and obese individuals, exenatide affects neural processing in visual cortex, both in early visual areas and in higher order areas. This effect may contribute to the known effect of GLP1 analogues on food-related behaviour., (© 2019 John Wiley & Sons, Ltd.)

Because of the unique mechanism of action of sodium-glucose co-transport inhibitors (SGLT2i), which is independent of insulin secretion and insulin action, members of this class of drugs effectively lower plasma glucose concentration when used in combination with all other antidiabetic agents, including insulin. Increased plasma ketone concentration has been reported in association with SGLT2i initiation, which, under certain clinical conditions, has developed into diabetic ketoacidosis. The daily insulin dose often is reduced at the time of initiating SGLT2i therapy in insulin-treated patients to avoid hypoglycaemia. However, reduction of insulin dose can increase the risk of ketoacidosis. In the present study, we examined the effect of the addition of dapagliflozin plus pioglitazone on plasma ketone concentration in insulin-treated T2DM patients and compared the results to the effect of dapagliflozin alone. A total of 18 poorly controlled, insulin-treated T2DM participants in the Qatar Study received dapagliflozin (10 mg) plus pioglitazone (30 mg), and 10 poorly controlled non-insulin-treated T2DM patients received dapagliflozin (10 mg) alone for 4 months. Dapagliflozin plus pioglitazone produced a robust decrease in HbA1c (-1.4%) and resulted in a 50% reduction in daily insulin dose, from 133 to 66 units, while dapagliflozin alone caused a 0.8% reduction in HbA1c. Dapagliflozin caused a four-fold increase in fasting plasma ketone concentration, while the combination of pioglitazone plus dapagliflozin was not associated with a significant increase (0.13 vs 0.15 mM) in plasma ketone concentration or in risk of hypoglycaemia. These results demonstrate that the addition of pioglitazone to dapagliflozin prevents the increase in plasma ketone concentration associated with SGLT2i therapy., (© 2018 John Wiley & Sons Ltd.)

Background Cardiac hypertrophy is an adaptive remodeling event that may improve or diminish contractile performance of the heart. Physiologic and pathologic hypertrophy yield distinct outcomes, yet both are dependent on caspase-directed proteolysis. This suggests that each form of myocardial growth may derive from a specific caspase cleavage event(s). We examined whether caspase 3 cleavage of the actin capping/severing protein gelsolin is essential for the development of pathologic hypertrophy. Methods and Results Caspase targeting of gelsolin was established through protein analysis of hypertrophic cardiomyocytes and mass spectrometry mapping of cleavage sites. Pathologic agonists induced late-stage caspase-mediated cleavage of gelsolin. The requirement of caspase-mediated gelsolin cleavage for hypertrophy induction was evaluated in primary cardiomyocytes by cell size analysis, monitoring of prohypertrophy markers, and measurement of hypertrophy-related transcription activity. The in vivo impact of caspase-mediated cleavage was investigated by echo-guided intramyocardial injection of adenoviral-expressed gelsolin. Expression of the N-terminal gelsolin caspase cleavage fragment was necessary and sufficient to cause pathologic remodeling in isolated cardiomyocytes and the intact heart, whereas expression of a noncleavable form prevents cardiac remodeling. Alterations in myocardium structure and function were determined by echocardiography and end-stage cardiomyocyte cell size analysis. Gelsolin secretion was also monitored for its impact on naïve cells using competitive antibody trapping, demonstrating that hypertrophic agonist stimulation of cardiomyocytes leads to gelsolin secretion, which induces hypertrophy in naïve cells. Conclusions These results suggest that cell autonomous caspase cleavage of gelsolin is essential for pathologic hypertrophy and that cardiomyocyte secretion of gelsolin may accelerate this negative remodeling response.

The present study aims to identify predictors for response to combination therapy with pioglitazone plus exenatide vs basal/bolus insulin therapy in T2DM patients who are poorly controlled with maximum/near-maximum doses of metformin plus a sulfonylurea. Participants in the Qatar study received a 75-g OGTT with measurement of plasma glucose, insulin and C-peptide concentration at baseline and were then randomized to receive either treatment with pioglitazone plus exenatide or basal/bolus insulin therapy for one year. Insulin secretion measured with plasma C-peptide concentration during the OGTT was the strongest predictor of response to combination therapy (HbA1c ≤ 7.0%) with pioglitazone plus exenatide. A 54% increase in 2-hour plasma C-peptide concentration above the fasting level identified subjects who achieved the glycaemic goal (HbA1c < 7.0%) with 82% sensitivity and 79% specificity. Only baseline HbA1c was a predictor of response to basal/bolus insulin therapy. Thus, the increment in 2-hour plasma C-peptide concentration above the fasting level provides a useful tool to identify poorly controlled T2DM patients who can achieve glycaemic control without insulin therapy, and thereby, can be used to individualize antihyperglycaemic therapy in poorly controlled T2DM patients., (© 2017 John Wiley & Sons Ltd.)

The sodium-glucose co-transporters (SGLTs) are responsible for the tubular reabsorption of filtered glucose from the kidney into the bloodstream. The inhibition of SGLT2-mediated glucose reabsorption is a novel and highly effective strategy to alleviate hyperglycaemia in patients with type 2 diabetes mellitus (T2DM). However, the effectiveness of SGLT2 inhibitor therapy is diminished due, in part, to a compensatory increase in the maximum reabsorptive capacity (Tm) for glucose in patients with T2DM. We hypothesized that this increase in Tm could be explained by an increase in the tubular expression of SGLT and glucose transporters (GLUT) in these patients. To examine this, we obtained human kidney biopsy specimens from patients with or without T2DM and examined the mRNA expression of SGLTs and GLUTs. The expression of SGLT1 is markedly increased in the kidney of patients with T2DM, and SGLT1 mRNA is highly and significantly correlated with fasting and postprandial plasma glucose and HbA1c. In contrast, our data demonstrate that the levels of SGLT2 and GLUT2 mRNA are downregulated in diabetic patients, but not to a statistically significant level. These important findings are clinically significant and may have implications for the treatment of T2DM using strategies that target SGLT transporters in the kidney., (© 2017 John Wiley & Sons Ltd.)

Aim: To examine metabolic factors that influence ketone production after sodium-glucose cotransport inhibitor (SGLT2) administration., Research Design and Methods: Fasting plasma glucose (FPG), insulin, glucagon, free fatty acid and ketone concentrations were measured in 15 type 2 diabetes mellitus (T2DM) and 16 non-diabetic subjects before and at day 1 and day 14 after treatment with empagliflozin., Results: Empagliflozin caused a 38 mg/dL reduction in FPG concentration in T2DM patients. However, it caused only a small but significant (7 mg/dL) reduction in the FPG concentration in impaired fasting glucose (IFG) subjects and did not affect FPG concentration in normal glucose tolerant (NGT) subjects. Empagliflozin caused a significant increase in mean plasma glucagon, free fatty acid (FFA) and ketone concentrations in T2DM subjects. However, empagliflozin did not cause a significant change in mean plasma insulin, glucagon or ketone concentrations in non-diabetic subjects. An index that integrates change in plasma glucose, insulin and FFA concentration at day 1 strongly correlates with plasma ketone concentration at day 1 (r = 0.85, P < .001) and day 14 (r = 0.63, r = 0.01) and predicts, with 86% sensitivity and 83% specificity, subjects at the top tertile for plasma ketone concentration after empagliflozin treatment., Conclusion: Results of the present study demonstrate that SGLT2 inhibition exerts different metabolic effects in non-diabetic individuals as compared to diabetic patients., (© 2017 John Wiley & Sons Ltd.)