C.J.J. Tack

Brain Lactate Concentration Falls in Response to Hypoglycemia in Patients With Type 1 Diabetes and Impaired Awareness of Hypoglycemia

Brain lactate may be involved in the development of impaired awareness of hypoglycemia (IAH), a condition that affects approximately 25% of patients with type 1 diabetes and increases the risk of severe hypoglycemia. The aim of this study was to investigate the effect of acute hypoglycemia on brain lactate concentration in patients with IAH as compared with those with normal awareness of hypoglycemia (NAH) and healthy control subjects (n = 7 per group). After an overnight fast, all subjects underwent a two-step hyperinsulinemic euglycemic (5.0 mmol/L)–hypoglycemic (2.8 mmol/L) glucose clamp. Brain lactate concentrations were measured continuously with 1H-MRS using a specific lactate detection method. Hypoglycemia generated symptoms in patients with NAH and healthy control subjects but not in patients with IAH. Brain lactate fell significantly by ∼20% in response to hypoglycemia in patients with type 1 diabetes with IAH but remained stable in both healthy control subjects and in patients with NAH. The fall in brain lactate is compatible with increased brain lactate oxidation providing an alternative fuel source during hypoglycemia, which may contribute to the impaired detection of hypoglycemia.

Insulin administered by needle-free jet injection corrects marked hyperglycaemia faster in overweight or obese patients with diabetes

To test whether jet injection of insulin resulted in faster correction of marked hyperglycaemia than when insulin is injected by a conventional pen in patients with diabetes.

A single bout of high-intensity interval training reduces awareness of subsequent hypoglycemia in patients with type 1 diabetes

High-intensity interval training (HIIT) has gained increasing popularity in patients with diabetes. HIIT acutely increases plasma lactate levels. This may be important, since the administration of lactate during hypoglycemia suppresses symptoms and counterregulation while preserving cognitive function. We tested the hypothesis that, in the short term, HIIT reduces awareness of hypoglycemia and attenuates hypoglycemia-induced cognitive dysfunction. In a randomized crossover trial, patients with type 1 diabetes and normal awareness of hypoglycemia (NAH), patients with impaired awareness of hypoglycemia (IAH), and healthy participants (n = 10 per group) underwent a hyperinsulinemic-hypoglycemic (2.6 mmol/L) clamp, either after a HIIT session or after seated rest. Compared with rest, HIIT reduced symptoms of hypoglycemia in patients with NAH but not in healthy participants or patients with IAH. HIIT attenuated hypoglycemia-induced cognitive dysfunction, which was mainly driven by changes in the NAH subgroup. HIIT suppressed cortisol and growth hormone responses, but not catecholamine responses to hypoglycemia. The present findings demonstrate that a single HIIT session rapidly reduces awareness of subsequent hypoglycemia in patients with type 1 diabetes and NAH, but does not in patients with IAH, and attenuates hypoglycemia-induced cognitive dysfunction. The role of exercise-induced lactate in mediating these effects, potentially serving as an alternative fuel for the brain, should be further explored.

Durable efficacy of liraglutide in patients with type 2 diabetes and pronounced insulin-associated weight gain: 52-week results from the Effect of Liraglutide on insulin-associated wEight GAiN in patients with Type 2 diabetes' (ELEGANT) randomized controlled trial

Pronounced weight gain frequently complicates insulin therapy in patients with type 2 diabetes (T2DM). We have previously reported that addition of liraglutide for 26 weeks can reverse insulin‐associated weight gain, decrease insulin dose and improve glycaemic control, as compared with continuation of standard insulin treatment.

Effect of Exercise-Induced Lactate Elevation on Brain Lactate Levels During Hypoglycemia in Patients With Type 1 Diabetes and Impaired Awareness of Hypoglycemia

Since altered brain lactate handling has been implicated in the development of impaired awareness of hypoglycemia (IAH) in type 1 diabetes, the capacity to transport lactate into the brain during hypoglycemia may be relevant in its pathogenesis. High-intensity interval training (HIIT) increases plasma lactate levels. We compared the effect of HIIT-induced hyperlacticacidemia on brain lactate during hypoglycemia between 1) patients with type 1 diabetes and IAH, 2) patients with type 1 diabetes and normal awareness of hypoglycemia, and 3) healthy participants without diabetes (n = 6 per group). All participants underwent a hypoglycemic (2.8 mmol/L) clamp after performing a bout of HIIT on a cycle ergometer. Before HIIT (baseline) and during hypoglycemia, brain lactate levels were determined continuously with J-difference–editing 1H-MRS, and time curves were analyzed using nonlinear mixed-effects modeling. At the beginning of hypoglycemia (after HIIT), brain lactate levels were elevated in all groups but most pronounced in patients with IAH. During hypoglycemia, brain lactate decreased ∼30% below baseline in patients with IAH but returned to baseline levels and remained there in the other two groups. Our results support the concept of enhanced lactate transport as well as increased lactate oxidation in patients with type 1 diabetes and IAH.

Liver fat content is linked to inflammatory changes in subcutaneous adipose tissue in type 2 diabetes patients

Patients with type 2 diabetes mellitus (T2DM) are typically overweight and have an increased liver fat content (LFAT). High LFAT may be explained by an increased efflux of free fatty acids from the adipose tissue, which is partly instigated by inflammatory changes. This would imply an association between inflammatory features of the adipose tissue and liver fat content.

Genetic determinants of impaired awareness of hypoglycemia in type 1 diabetes

Objective It is likely that impaired awareness of hypoglycemia (IAH) and severe hypoglycemia are in part determined by genetic factors. The aim of this study was to investigate candidate genes for associations with IAH and severe hypoglycemia in a cohort of patients with type 1 diabetes. Participants and methods Consecutive patients with type 1 diabetes were genotyped for single-nucleotide polymorphisms in or near the genes for the &bgr;1 and &bgr;2 adrenergic receptor (ADRB1, ADRB2), SORCS1, and BNC2, and for the insertion/deletion polymorphism in the ACE gene. IAH and severe hypoglycemia were assessed using a validated questionnaire. Results Of 486 patients, 32.5% were classified as having IAH. The Arg16Gly polymorphism of ADRB2 was associated with IAH (odds ratio: 1.49, 95% confidence interval: 1.01–2.20, P=0.046) Gly16 (GG) versus carriers of the A allele. In a haplotype analysis, the association was the highest in patients with GG at position 16 and heterozygous at position 27 (odds ratio: 2.19, 95% confidence interval: 1.33–3.61, P=0.03). There were no associations between IAH and other genes, and none of the studied genes was associated with severe hypoglycemia. Conclusion Genotypes at two variants of ADRB2 are associated with IAH. This association is comparable with the risk of classical risk factors for IAH.

Correctie van substantiële hyperglykemie met insuline bij patiënten met diabetes; is controle na één uur zinvol?

SamenvattingAchtergrond Bij correctie van substantiële hyperglykemie met een, al dan niet geïndividualiseerde, insulinedosis is het gebruikelijk om het effect na één uur te evalueren. Wij onderzochten wat het glucoseverlagende effect na één uur is bij patiënten bij wie een hyperglykemie met een individueel berekende dosis werd gecorrigeerd. Methode We analyseerden data van tien patiënten met type 1-diabetes en tien patienten met type 2-diabetes die hadden deelgenomen aan een gerandomiseerd, gecontroleerd cross-over-onderzoek dat twee insulinepennen vergeleek voor de correctie van hyperglykemie. Insuline aspart werd subcutaan toegediend in een individuele dosis die rekening hield met insulinegevoeligheid en glucosetoxiciteit. Plasmaglucosewaarden werden gedurende zes uur met intervallen van vijf tot tien minuten gemeten. Deze analyse gebruikte alleen data verkregen met een conventionele insulinepen. Resultaten De gemiddelde plasmaglucosewaarde bij de start van de studie was 20.4 ± 0.5 mmol/l. Na injectie van 20.3 ± 2.4 eenheden insuline daalde de glucosewaarde na één uur met slechts 3.2 ± 0.5 mmol/l en na twee uur met 7.3 ± 0.7 mmol/l. Bij 60% van de patiënten daalde de glucosewaarde gedurende het eerste uur zelfs minder dan 3 mmol/l. Na 323.5 ± 12.1 min daalde de glucose met 14.2 ± 0.6 mmol/l tot een nadir van 6.4 ± 0.4 mmol/l. Bij 85% van de patiënten zorgde het algoritme voor optimale correctie (laagst bereikte glucose 4.8-10 mmol/l); 15% van de patiënten had glucosetoediening nodig om een hypoglykemie te voorkomen. Conclusie Ondanks de hoge individuele insulinedosis en optimale correctie was bij de meeste patiënten de initiële glucosedaling slechts bescheiden. De klinische relevantie van het controleren van de bloedglucosewaarde na één uur lijkt beperkt, zelfs bij snelwerkende insulineanalogen.

Prevalence of Impaired Awareness of Hypoglycemia and Severe Hypoglycemia among People with Type 2 Diabetes Treated with Insulin—The Dutch Diabetes Pearl Cohort

Aim: Most people with type 2 diabetes eventually require insulin treatment because of progressive loss of beta-cell function. The most common adverse effect of insulin therapy is hypoglycemia. Recurrent hypoglycemia may lead to impaired awareness of hypoglycemia (IAH) and a consequently high risk for severe hypoglycemia. The aim of this study was to determine the prevalence of IAH and severe hypoglycemia in a large cohort of people with insulin-treated type 2 diabetes. Methods: The Dutch Diabetes Pearl is a contemporary cohort of people with type 2 diabetes from primary, secondary and tertiary medical centers in the Netherlands. We collected data from people on insulin therapy who had completed the validated Dutch version of the Clarke questionnaire on IAH, where 3 out of 5 points indicate IAH. Descriptive statistics, T-tests and Chi-square tests were performed. Results: Our study included 1923 patients of whom 59% were men. Median age was 62.1 years (interquartile range 55.1-68.3), median diabetes duration was 13.9 years (8.8-20.1) and median HbA 1c was 7.6 % (7.0-8.5). 2individuals (10.8%) were classified as having IAH; these people were more likely to be non-Caucasian and have a lower educational level, and less likely to have a partner. Severe hypoglycemia was reported in 617 patients (32.1%) and severe hypoglycemia requiring medical intervention in the past year in 166 patients (8.6%). People with severe hypoglycemia were more likely to be non-Caucasian, to have a lower educational level, to have a history of cardiovascular events and neuropathic pain, and to use over 10 different types of drugs. No significant associations between HbA 1c -levels and IAH or severe hypoglycemia were observed. Conclusion: IAH and severe hypoglycemia are common in people with type 2 diabetes treated with insulin. Non- Caucasian ethnicity, lower educational level, and being single may be risk factors for IAH in patients with type 2 diabetes. Disclosure L. van Meijel: None. F. de Vegt: None. C. Tack: Advisory Panel; Self; Merck Sharp & Dohme Corp., Novo Nordisk A/S, AstraZeneca. Research Support; Self; AstraZeneca. Speaker9s Bureau; Self; Novo Nordisk A/S. E.J. Abbink: None. F. Rutters: None. J.M. Dekker: None. B.H. Wolffenbuttel: None. F. Holleman: Other Relationship; Self; Sanofi-Aventis, Bioton, AstraZeneca. J. DeVries: Research Support; Self; Dexcom, Inc., Medtronic, Novo Nordisk A/S. Advisory Panel; Self; Novo Nordisk A/S. Speaker9s Bureau; Self; Novo Nordisk A/S, Roche Diabetes Care Health and Digital Solutions. Advisory Panel; Self; Sanofi. Research Support; Self; Senseonics. Speaker9s Bureau; Self; Senseonics. Advisory Panel; Self; Zealand Pharma A/S. N. Masurel: None. H. Pijl: None. B. Ozcan: None. B. Silvius: None. B.E. de Galan: Research Support; Self; AstraZeneca, Sanofi. Advisory Panel; Self; Novo Nordisk A/S.

A comparison of the pharmacodynamic profiles of jet-injected regular human insulin versus conventionally administered insulin aspart in healthy volunteers

AIMS Rapid-acting insulin analogues are generally preferred over regular human insulin because of their more immediate onset of action and shorter time-action profile. However, these analogues may not always be tolerated by or universally available for people with insulin-requiring diabetes. Jet injection has been demonstrated to facilitate faster insulin absorption. We determined whether administration of regular human insulin by jet injection achieves the same pharmacological properties as that of a rapid-acting insulin analogue. METHODS Twenty healthy volunteers received regular human insulin (0.2units/kg) by jet injection. Glucose 20% was infused intravenously to maintain euglycaemia over six hours. The glucose infusion rates (GIR) were determined to compare pharmacological profiles. These profiles were compared with data from two other studies in which a similar dose of insulin aspart was administered by conventional pen. RESULTS Regular human insulin by jet injection had a faster onset of glucose-lowering effect compared to aspart by conventional pen (T-GIR50%, 30.8±2.9 versus 43.1±3.2min, P<0.01). There were no differences in time to maximal GIR (106.1±11.9 versus 95.8±9.2min, P=0.50), maximal GIR (8.6±0.7 versus 7.7±0.7mg/kg/min, P=0.0.33), total glucose-lowering effect (101.0±9.8 versus 87.6±7.0g, P=0.28), and time until 50% of glucose disposal (144.8±5.6 versus 151.3±5.1min, P=0.39). CONCLUSIONS Jet-injected regular human insulin had a pharmacological profile that was essentially not dissimilar from that of aspart insulin administered by conventional pen, and can therefore be used as an alternative for conventionally administered rapid-acting insulin analogues.