Switching from Neutral Protamine Hagedorn (NPH) Insulin to Insulin Glargine 300 U/mL in Older and Younger Patients with Type 2 Diabetes: A Post Hoc Analysis of a Multicenter, Prospective, Observational Study.

INTRODUCTION: Older age and longer disease duration are key risk factors for hypoglycemia in patients with type 2 diabetes (T2D) who receive insulin. Previous studies have shown that insulin glargine 300 U/mL (Gla-300) improves glycemic control and reduces the risk of hypoglycemia, but whether this effect is observed in older patients switching from neutral protamine Hagedorn (NPH) insulin is unclear. METHODS: In this multicenter, observational study involving patients with T2D aged ≥ 18 years with glycated hemoglobin (HbA1c) ≥ 8%, we compared the safety and effectiveness of switching from NPH insulin to Gla-300 in subgroups of patients differing by age (< 65 vs. ≥ 65 years) and duration of diabetes (≤ 13 vs. > 13 years). RESULTS: A total of 469 participants were included in the study. From baseline to 6 months after switching to Gla-300, mean HbA1c decreased from 9.23% to 8.13% (p < 0.001) among patients aged ≤ 65 years (224 patients), and from 9.15% to 8.20% (p < 0.001) among those aged > 65 years (245 patients). The proportion of patients with ≥ 1 episodes of hypoglycemia decreased from 19.1% to 13.6% (p = 0.11) among those aged ≤ 65 years, and from 26.9% to 13.0% (p < 0.001) among those aged > 65 years; the reduction was significantly greater in those aged > 65 years (p = 0.001). The reduction in HbA1c was greater in those with a disease duration ≤ 13 years (p = 0.007), but the reduction in hypoglycemia was greater in those with a disease duration > 13 years (p < 0.0003). CONCLUSION: The switch from NPH insulin to Gla-300 improved glycemic control in older patients with T2D and in those with a longer disease duration. Older patients with T2D and those with a longer disease duration benefited even more from the switch to Gla-300 than younger patients and those with a shorter disease duration, with significantly greater reductions in the risk of hypoglycemia.

Switching from Neutral Protamine Hagedorn Insulin to Insulin Glargine 300 U/mL Improves Glycaemic Control and Reduces Hypoglycaemia Risk: Results of a Multicentre, Prospective, Observational Study.

Type 2 diabetes mellitus (T2DM) is a major cause of morbidity and mortality worldwide and is an important public health issue. A significant proportion of insulin-treated patients with T2DM do not reach target glycated haemoglobin (HbA1c) values, which ultimately increases their risk of long-term microvascular and macrovascular complications. One potential option to improve diabetes control in these patients may be the use of new insulin formulations including second-generation basal insulin analogues such as insulin glargine 300 U/mL (Gla-300). Several published randomised controlled trials have assessed the clinical effectiveness of Gla-300, mostly versus insulin glargine 100 U/mL as well as insulin degludec. However, there is limited information about the real-world effectiveness of Gla-300 when patients are transitioned directly from neutral protamine Hagedorn (NPH) human basal insulin. The primary objective of this study was to evaluate the effectiveness of Gla-300, defined as the percentage of participants with an HbA1c reduction of ≥0.5%, 6 months after switching from NPH insulin, in participants with T2DM. Secondary objectives included the safety assessment based on the percentage of patients experiencing ≥1 episodes and the number of hypoglycaemic episodes by category: severe, symptomatic, symptomatic confirmed, diurnal or nocturnal, change in body weight, and insulin dose. A total of 469 participants completed the 6-month observation period. Mean baseline HbA1c was 9.19%. The percentage of participants with a ≥0.5% improvement in HbA1c from baseline was 71.7% at 6 months. Mean HbA1c decreased at 3 and 6 months by 0.77% (±0.98) and 1.01% (±1.12), respectively (p < 0.00001 versus baseline), while fasting glycaemia decreased by 32 mg/dL and 37 mg/dL, respectively (p < 0.00001 versus baseline). There were moderate increases in the doses of both Gla-300 and, if used, short-acting insulins during the 6 months of observation. The percentage of participants with ≥1 hypoglycaemia event during the preceding 4 weeks decreased significantly from baseline to 3 and 6 months, as did the proportion with symptomatic hypoglycaemia at night (p < 0.00001 versus baseline). No participants had severe hypoglycaemia after a switch to Gla-300. Body mass, waist and hip circumferences, and waist : hip ratio did not change significantly. In conclusion, this large, prospective, observational study demonstrated that switching from NPH insulin to Gla-300 resulted in a significant improvement in HbA1c, with only a moderate increase in insulin dose, a decreased risk of hypoglycaemia, and no increase in body weight.

Knockdown of PRAS40 inhibits insulin action via proteasome-mediated degradation of IRS1 in primary human skeletal muscle cells.

AIMS/HYPOTHESIS: The proline-rich Akt substrate of 40 kDa (PRAS40) is a component of the mammalian target of rapamycin complex 1 (mTORC1) and among the most prominent Akt substrates in skeletal muscle. Yet the cellular functions of PRAS40 are incompletely defined. This study assessed the function of PRAS40 in insulin action in primary human skeletal muscle cells (hSkMC). METHODS: Insulin action was examined in hSkMC following small interfering RNA-mediated silencing of PRAS40 (also known as AKT1S1) under normal conditions and following chemokine-induced insulin resistance. RESULTS: PRAS40 knockdown (PRAS40-KD) in hSkMC decreased insulin-mediated phosphorylation of Akt by 50% (p < 0.05) as well as of the Akt substrates glycogen synthase kinase 3 (40%) and tuberous sclerosis complex 2 (32%) (both p < 0.05). Furthermore, insulin-stimulated glucose uptake was reduced by 20% in PRAS40-KD myotubes (p < 0.05). Exposing PRAS40-KD myotubes to chemokines caused no additional deterioration of insulin action. PRAS40-KD further reduced insulin-mediated phosphorylation of the mTORC1-regulated proteins p70S6 kinase (p70S6K) (47%), S6 (43%), and eukaryotic elongation 4E-binding protein 1 (100%), as well as protein levels of growth factor receptor bound protein 10 (35%) (all p < 0.05). The inhibition of insulin action in PRAS40-KD myotubes was associated with a reduction in IRS1 protein levels (60%) (p < 0.05), and was reversed by pharmacological proteasome inhibition. Accordingly, expression of the genes encoding E3-ligases F-box protein 32 (also known as atrogin-1) and muscle RING-finger protein-1 and activity of the proteasome was elevated in PRAS40-KD myotubes. CONCLUSIONS/INTERPRETATION: Inhibition of insulin action in PRAS40-KD myotubes was found to associate with IRS1 degradation promoted by increased proteasome activity rather than hyperactivation of the p70S6K-negative-feedback loop. These findings identify PRAS40 as a modulator of insulin action.

Generation of reactive oxygen species by endothelial and smooth muscle cells: influence of hyperglycemia and metformin.

There is evidence that reactive oxygen intermediates (ROI) play an important role in the pathogenesis of vascular complications in diabetes. On the other hand, metformin, one of the most often used antidiabetic compounds has not only been shown to reduce the risk for vascular complications, but in addition these protective effects are largely independent of its well-known antihyperglycemic action. Therefore, to explain the vasculoprotective effects of metformin, a direct antioxidative action of this compound has been suggested. We show here that human endothelial cells (HUVEC) generate ROI not only in response to high glucose (30 mmol/l glucose), but also in response to palmitic acid, and advanced glycation end-products (carboxymethyllysine and S100 proteins). Metformin inhibited the production of ROI in response to all these stimuli. By double staining-dichlorofluorescein as marker of ROI and Mitotracker CMH-Ros for mitochondria-the mechanism of ROI generation was analyzed in more detail in smooth muscle cells. Our data suggest that ROI are generated by uncoupling of the mitochondrial respiratory chain as well as by activation of the cytosolic NADPH-oxidase. A complete inhibition of ROI generation is only achieved by simultaneous inhibition of the mitochondrial electron flux (theonyltrifluoroacetone) and NADPH-oxidase (apocynin). Our data suggest that the various processes contributing to generation of ROI are closely linked. Activation of AMP kinase may represent an important mechanism to understand the antioxidative effects of metformin on the mitochondrial and cytosolic generation of ROI.

[Appearance of undiagnosed diabetes mellitus in the population of professionally active people in the urban areas]. / Wystepowanie cukrzycy nieznanej w populacji czynnych zawodowo osób w srodowisku miejskim.

Diabetes remains a great social and clinical problem. Therefore, there is a need to focus our efforts on prevention of the disease, especially of type 2 diabetes. Type 2 diabetes is characterized by accelerated development of atherosclerotic changes (macroangiopathy). Hyperglycaemia, hypertension, hyperlipidaemia and hyperfibrinogenaemia also play an important role in the development of macroangiopathy. Hyperinsulinemia, which accompanies the visceral type of obesity, is characteristic of type 2 diabetes. Considering all the above mentioned findings, prevention of type 2 diabetes should be based on the population level, concentrating especially on the groups with increased risk of obesity and/or diabetes (early primary prevention). However, in the present conditions, it seems that screening studies can be conducted only in the groups with high risk of type 2 diabetes (late primary prevention). They allow for relatively early detection of disturbances in carbohydrate metabolism. The aim of the study was to assess the prevalence of undiagnosed diabetes in the population of professionally active inhabitants in Pleszew. 2700 subjects, aged 35-65 years, entered the study. All patients claimed to be healthy. In the first phase of the study, the fasting capillary glycaemia was tested. Fasting blood glucose or oral glucose tolerance test was performed in all cases which fasting capillary glucose was higher then 5.5 mmol/l (100 mg/dl). The screening study revealed 91 cases with glycaemia higher than 6.8 mmol/l (3.4%). 387 subjects (14.3%) with glycaemia ranging from 5.5 to 6.8 mmol/l were qualified to perform the oral glucose tolerance test. Out of this group 138 persons did not come to the laboratory. Thus, the test was conducted in 249 causes (64.3%). The results obtained excluded another 197 subjects as no disturbances in the glucose metabolism were found. Based on the results of the oral glucose tolerance test 39 patients were diagnosed to have an impaired glucose tolerance (2 h glycaemia from 7.8 to 11.1 mmol/l) and in 13 cases diabetes was diagnosed (2 h glycaemia above 11.1 mmol/l). In conclusion, the screening study performed in professionally active adults aged > 35 years, who claimed to be healthy, clinically latent diabetes or impaired glucose tolerance was found in 5.3% cases. 92.8% patients with IGT or diabetes were obese or overweight (BMI > 25 kg/m2) and 32.4% had hypertension (RR > 140/90 mm Hg). In 64% of subjects the serum cholesterol concentration was higher than 5.2 mmol/l and in 18% subjects HDL cholesterol concentration was lower than 1.0 mmol/l and LDL cholesterol higher than 3.5 mmol/l. Elevated triglycerides concentration > 2.0 mmol/l was observed in 30%. In the group with newly diagnosed diabetes, mean age was 55.0 +/- 9.2 years. 27.9% had positive family history of diabetes, 26.5% were smokers, 44.1% were found to have disturbed lower limbs circulation and 30.9% had abnormal feeling of vibration, 7.8% patients with diabetes had symptoms of diabetic retinopathy and 20.1% had microalbuminuria. Body mass index (BMI) in newly diagnosed diabetic patients was 31.6 +/- 5.3 kg/m2 and waist to hip ratio (WHR) was 0.94 +/- 0.41 and indicated the visceral type of obesity. Mean fasting glycaemia was equal 7.26 +/- 1.93 mmol/l and mean HbA1c value was 6.2 +/- 0.7%. It exceeded the laboratory normal value in 17.6% of cases. In 91 patients with fasting glycaemia higher then 15.5 mmol/l insulinaemia was also assessed; its level was elevated in 10 patients. The project of study was prepared in 1996. However, in 1999 the new criteria for diagnosis and treatment of type 2 diabetes were established. The results of the performed study indicate that screening towards diabetes should be performed in subjects aged > 35 years with overweight or obesity and at least one additional risk factor of arteriosclerosis.