Influence of acute alcohol ingestion on the hormonal responses to modest hypoglycaemia in patients with Type 1 diabetes.

AIMS: To determine whether mild alcohol intoxication (45-50 mg/dl) influences counterregulatory hormone responses to moderate hypoglycaemia (2.8 mmol/l)in patients with Type 1 diabetes. METHODS: Seventeen subjects (14 male, age range 21-46 years) with Type 1 diabetes underwent four hyperinsulinaemic glucose clamps: euglycaemia with placebo; euglycaemia with alcohol (0.4 g/kg); hypoglycaemia (2.8 mmol/l for 65 min)with placebo; and hypoglycaemia (2.8 mmol/l for 65 min) with alcohol (0.4 g/kg).Arterialized venous blood samples were taken for measurement of insulin and counterregulatory hormones. RESULTS: During hypoglycaemia, peak growth hormone concentrations were significantly lower after alcohol compared with placebo (14.3 +/- 2.9 vs.25.9 +/- 3.4 microg/l,P< 0.001) associated with reduced insulin sensitivity in both hypoglycaemia and euglycaemia studies. CONCLUSIONS: We found an attenuated growth hormone response to hypoglycaemia associated with mild alcohol intoxication. Although this may potentially contribute to impaired recovery of glucose after hypoglycaemia in patients with Type 1 diabetes, it appears to be offset by a reduction in insulin action.     

An Analysis of the Glucagon Response to Hypoglycaemia in Patients with Type 1 Diabetes and in Healthy Subjects

The study aimed to analyse the glucagon response during hypoglycaemia in relation to gender, level of hypoglycaemia, and hyperinsulinaemia as well as its relation to other counterregulatory hormones in patients with Type 1 diabetes and in nondiabetic subjects. Mild hypoglycaemia was induced by an i.v. insulin infusion (244 pmol kg^?1h^?1) for 180 min in 43 Type 1 diabetic patients and 22 nondiabetic subjects. Venous blood glucose, plasma free insulin, glucagon, adrenaline, noradrenaline, growth hormone, and cortisol were measured every 15–30 min. The hormonal responses during hypoglycaemia were evaluated from the incremental areas under their respective curves. There was a linear correlation between the glucagon response and the decremental area of blood glucose (p < 0.005), but the slope of the regression line in the diabetic group was less steep than in the controls (p < 0.5), and, in spite of the deeper hypoglycaemia in the diabetic groups, their glucagon response was diminished (p < 0.05). Plasma, adrenaline, growth hormone and cortisol all increased during hypoglycaemia. The glucagon response correlated with the responses of growth hormone and cortisol in both groups, while it was positively correlated with the adrenaline response (p < 0.001) and inversely with the plasma insulin (p < 0.001) only in the diabetic patients. Although the insulin infusion rate was identical, the female diabetic patients had a lower metabolic clearance rate of insulin as compared with the males (p < 0.05). There was no statistical difference in the counterregulatory hormone responses between males and females in neither of the groups. In conclusion, this study suggests that the glucagon response to hypoglycaemia in Type 1 diabetic patients, may be suppressed by circulating insulin within its therapeutic range, and stimulated by the simultaneously secreted adrenaline. Furthermore, female Type 1 diabetic patients have a lower metabolic clearance rate of insulin than males, yielding a more pronounced hypoglycaemia in response to the same dose of insulin, although this study does not provide evidence of a gender difference in the responsiveness of counterregulatory hormones to hypoglycaemia.     

Lack of preservation of higher brain function during hypoglycaemia in patients with intensively-treated IDDM

Summary Severe hypoglycaemia with cognitive dysfunction is 3 times more common in intensively, rather than conventionally, treated insulin-dependent diabetes mellitus (IDDM). To investigate the effect of diabetes control on higher brain function during acute hypoglycaemia, we studied one of the earliest detectable changes in cognitive function, i.e. the four-choice reaction time, and symptomatic and hormonal responses during euglycaemic and hypoglycaemic clamping in human subjects. There were no changes in symptoms or counterregulatory hormones and four-choice reaction time was stable during 220 min of euglycaemic insulin clamping in five men with IDDM, with a coefficient of variation of less than 2.2% (1% for accuracy) for the cognitive function test. During stepped hypoglycaemic clamping however, hormonal responses and subjective awareness of hypoglycaemia occurred in all groups but started at much lower blood glucose concentrations in eight intensively-treated diabetic subjects (Group 1) than in ten conventionally-treated (Group 2) or in eight non-diabetic subjects (Group 3). For example, for adrenaline, plasma glucose thresholds were 2.7±0.2 vs 3.4±0.2 and 3.2±0.1 mmol/l, respectively, p<0.05, Group 1 vs Groups 2 or 3 and for subjective awareness of hypoglycaemia 2.3±0.2 vs 3.0±0.1 and 3.2±0.1 mmol/l, p 0.003), as in previous studies. In contrast, deterioration in reaction time occurred at 3.2±0.3, 3.2±0.2 and 3.0+0.2 mmol/l, respectively (p=NS), thus occurring at higher glucose levels than subjective awareness in the intensively-treated subjects only. The altered hierarchy of responses to hypoglycaemia in well-controlled intensively-treated diabetes explains the increased risk of severe hypoglycaemia without warning seen in such patients.Abbreviations IDDM Insulin-dependent diabetes mellitus     

Glucose counterregulation in Type 2 diabetes mellitus.

Glucose counterregulatory failure and hypoglycaemia unawareness frequently complicate treatment of Type 1 diabetes mellitus, especially when aiming for intensive metabolic control. Since tight metabolic control reduces microvascular long-term complications in Type 2 diabetes mellitus, the integrity of glucose counterregulation in Type 2 diabetic patients is important. Using a Medline search, we identified 12 studies in which counterregulatory responses to insulin-induced hypoglycaemia were compared between Type 2 diabetic patients and appropriate controls. A review of these studies showed that some patients with Type 2 diabetes mellitus develop mild counterregulatory dysfunction and reduced awareness of insulin-induced hypoglycaemia. Some studies suggested an association between counterregulatory impairment and intensity of metabolic control. We speculate that the relatively low frequency of (severe) hypoglycaemic events in Type 2 diabetes may explain why glucose counterregulation remains unaffected in most patients. We hypothesize that residual beta-cell reserve and insulin resistance provide protection against severe hypoglycaemia and limit impaired counterregulation. Diabet. Med. 18, 519-527 (2001)     

Counterregulation in Type 2 (non-insulin-dependent) diabetes mellitus. Normal endocrine and glycaemic responses,up to ten years after diagnosis

Summary We have examined hormonal and metabolic responses to insulin-induced hypoglycaemia in 10 Type 2 (non-insulin-dependent) diabetic patients treated with tablets and 10 age, sex and weight matched control subjects. Diabetic patients were under 110% ideal body weight, had no autonomie neuropathy and were well controlled (HbA₁, 7.1±0.2%). After the diabetic patients were kept euglycaemic by an overnight insulin infusion, hypoglycaemia was induced in both groups by intravenous insulin at 30 mU·m^–2·min^–1 for 60 min and counterregulatory responses measured for 150 min. There were no significant differences between diabetic patients and control subjects in the rate of fall (3.3±0.3 vs 4.0±0.3 mmol·1^–1·h^–1), nadir (2.4±0.2 vs 2.3±0.1 mmol/l) and rate of recovery (0.027±0.002 vs 0.030±0.003 mmol·1^–1·min^–1) of blood glucose. Increments of glucagon (60.5±5.7 vs 70±9.2 ng/l) and adrenaline (1.22±0.31 vs 1.45±0.31 nmol/l) were similar in both groups. When tested using this model, patients with Type 2 diabetes, without microvascular complications and taking oral hypoglycaemic agents show no impairment of the endocrine response and blood glucose recovery following hypoglycaemia.     

Low HDL‐cholesterol is common in European Type 2 diabetic patients receiving treatment for dyslipidaemia: data from a pan‐European survey

Aims To measure the prevalence of low high‐density lipoprotein (HDL)‐cholesterol (men < 1.03 mmol/l; women < 1.29 mmol/l) in European Type 2 diabetic patients receiving treatment for dyslipidaemia. Methods The pan‐European Survey of HDL‐cholesterol measured lipids and other cardiovascular risk factors in 3866 patients with Type 2 diabetes and 4436 non‐diabetic patients undergoing treatment for dyslipidaemia in 11 European countries. Results Diabetic patients were more likely to be obese or hypertensive than non‐diabetic patients. Most patients received lifestyle interventions (87%) and/or a statin (89%); treatment patterns were similar between groups. Diabetic patients had [means (SD)] lower HDL‐cholesterol [1.22 (0.37) vs. 1.35 mmol/l (0.44) vs. non‐diabetic patients, P < 0.001] and higher triglycerides [2.32 (2.10) vs. 1.85 mmol/l (1.60), P < 0.001]. More diabetic vs. non‐diabetic patients had low HDL‐cholesterol (45% vs. 30%), high triglycerides (≥ 1.7 mmol/l; 57% vs. 42%) or both (32% vs. 19%). HDL‐cholesterol < 0.9 mmol/l was observed in 18% of diabetic and 12% of non‐diabetic subjects. Differences between diabetic and non‐diabetic groups were slightly greater for women. LDL‐ and total cholesterol were lower in the diabetic group [3.02 (1.05) vs. 3.30 mmol/l (1.14) and 5.12 (1.32) vs. 5.38 mmol/l (1.34), respectively, P < 0.001 for each]. Conclusions Low HDL‐cholesterol is common in diabetes: one in two diabetic women has low HDL‐cholesterol and one diabetic man in four has very low HDL‐cholesterol. Management strategies should include correction of low HDL‐cholesterol to optimize cardiovascular risk in diabetes.     

Short‐term nocturnal hypoglycaemia increases morning food intake in healthy humans

Aims Hypoglycaemia during wakefulness increases hunger and food intake. Patients with Type 1 diabetes mellitus are at high risk of recurrent hypoglycaemia and weight gain. Given the background of frequent hypoglycaemic episodes during night‐time sleep in diabetic patients, we investigated morning food intake after nocturnal hypoglycaemia. Methods We tested 16 healthy normal‐weight subjects (eight women) on three nights. A linear fall in plasma glucose to a nadir of 2.2 mmol/l within 60 min was induced by insulin infusion immediately after sleep onset (‘early hypo’) or after about 3.5 h of sleep (‘late hypo’). On a control night, no hypoglycaemia was induced. Spontaneous food intake at a breakfast buffet was registered on the subsequent morning. Results Compared with the control condition (700 ± 93 kcal), subjects ate more after ‘late hypo’ (867 ± 108 kcal; P = 0.041), but not after ‘early hypo’ (852 ± 111 kcal; P = 0.130). Analyses of macronutrient fractions revealed that in comparison with the control condition, subjects ate significantly more carbohydrates after both ‘late hypo’ (277 ± 25 kcal vs. 206 ± 23 kcal, P < 0.001) and ‘early hypo’ (245 ± 23 kcal, P = 0.048), with this effect being more pronounced after late than early nocturnal hypoglycaemia (P = 0.026). Conclusions In healthy subjects, nocturnal hypoglycaemia during sleep stimulates spontaneous food intake the following morning, with carbohydrate intake being especially affected. Effects were more pronounced after ‘late hypo’, suggesting the influence of temporal dynamics. Although healthy non‐diabetic subjects were studied, similar mechanisms may contribute to the frequently observed body weight gain in insulin‐treated diabetic patients.     

Human insulin: much ado about hypoglycaemia (un)awareness

Summary The biological effects, hypoglycaemic symptoms, endocrine counterregulatory responses and glucose recovery following the injection of purified porcine and human insulin preparations were compared in a number of controlled clinical investigations and prospective clinical trials. In these studies involving healthy volunteers, Type 1 (insulin-dependent) diabetic patients on continuous subcutaneous insulin infusion or intensified conventional insulin therapy and insulin treated Type 2 (non-insulin-dependent) diabetic patients, no differences with regard to biological effects, counterregulatory responses, hypoglycaemic awareness or the long-term incidence of severe hypoglycaemia between porcine and human insulin preparations were identified. These data fail to confirm any specific risk of severe hypoglycaemia attributable to the use of human insulin preparations in the treatment of patients with diabetes mellitus.     

Regional variations in definitions and rates of hypoglycaemia: findings from the global HAT observational study of 27 585 people with Type 1 and insulin‐treated Type 2 diabetes mellitus

Aim

To determine participant knowledge and reporting of hypoglycaemia in the non‐interventional Hypoglycaemia Assessment Tool (HAT) study.

Methods

HAT was conducted in 24 countries over a 6‐month retrospective/4‐week prospective period in 27 585 adults with Type 1 or insulin‐treated Type 2 diabetes mellitus. Participants recorded whether hypoglycaemia was based on blood glucose levels, symptoms or both.

Results

Hypoglycaemia rates were consistently higher in the prospective compared with the retrospective period. Most respondents (96.8% Type 1 diabetes; 85.6% Type 2 diabetes) knew the American Diabetes Association/European Association for the Study of Diabetes hypoglycaemia definition, but there were regional differences in the use of blood glucose measurements and/or symptoms to define events. Confirmed symptomatic hypoglycaemia rates were highest in Northern Europe/Canada for Type 1 diabetes (63.9 events/year) and in Eastern Europe for Type 2 diabetes (19.4 events/year), and lowest in South East Asia (Type 1 diabetes: 6.0 events/year; Type 2 diabetes: 3.2 events/year). Unconfirmed symptomatic hypoglycaemia rates were highest in Eastern Europe for Type 1 diabetes (5.6 events/year) and South East Asia for Type 2 diabetes (4.7 events/year), and lowest for both in Russia (Type 1 diabetes: 2.1 events/year; Type 2 diabetes: 0.4 events/year). Participants in Latin America reported the highest rates of severe hypoglycaemia (Type 1 diabetes: 10.8 events/year; Type 2 diabetes 3.7 events/year) and severe hypoglycaemia requiring hospitalization (Type 1 diabetes: 0.56 events/year; Type 2 diabetes: 0.44 events/year). The lowest rates of severe hypoglycaemia were reported in South East Asia (Type 1 diabetes: 2.0 events/year) and Northern Europe/Canada (Type 2 diabetes: 1.3 events/year), and the lowest rates of severe hypoglycaemia requiring hospitalization were in Russia (Type 1 diabetes: 0.15 events/year; Type 2 diabetes: 0.09 events/year). The blood glucose cut‐off used to define hypoglycaemia varied between regions (Type 1 diabetes: 3.1–3.6 mmol/l; Type 2 diabetes: 3.5–3.8 mmol/l).

Conclusions

Under‐reporting of hypoglycaemia rates in retrospective recall and regional variations in participant definitions of hypoglycaemia may contribute to the global differences in reported rates. Discrepancies between participant definitions and guidelines may highlight a need to redefine hypoglycaemia criteria. (Clinical Trials Registry No: NCT01696266).     

Safety and efficacy of insulin glargine (HOE 901) versus NPH insulin in combination with oral treatment in Type 2 diabetic patients

Aims A European, randomized, 29‐centre, open‐label study compared the safety and efficacy of two formulations of insulin glargine and neutral protamine Hagedorn (NPH) human insulin, in combination with oral agents, in patients with Type 2 diabetes mellitus (DM). Methods Two‐hundred‐and‐four patients with Type 2 DM, in whom oral treatment alone was inadequate, were randomized to insulin glargine with 30 µg/ml zinc [insulin glargine (30)], or insulin glargine with 80 µg/ml zinc [insulin glargine (80)] or NPH insulin subcutaneously once daily. Insulin was titrated to aim for fasting blood glucose (FBG) values between 4 and 7 mmol/l. All participants received oral therapy during the 3‐week titration phase and 1‐week maintenance phase of the trial. Results No differences between treatment groups were observed in adjusted mean fasting plasma glucose; significant decreases of 3.4 mmol/l, 3.5 mmol/l and 3.1 mmol/l were observed within the insulin glargine (30), insulin glargine (80) and NPH insulin groups, respectively (P < 0.0001 in each case). No differences between groups, but significant changes within groups, were observed in self‐monitored FBG, mean FBG, blood glucose profile, stability of FBG, nocturnal blood glucose, fasting serum C‐peptide, non‐esterified fatty acids, haemoglobin A_1c, fructosamine and fasting serum insulin. A significantly greater proportion of NPH insulin patients experienced symptomatic nocturnal hypoglycaemia (19.1 NPH group vs. 7.3% glargine groups; P = 0.0123). Both insulins were well tolerated; one patient in each group experienced an injection site reaction. Conclusions Insulin glargine is as safe and effective as NPH insulin given once daily and in this study caused fewer episodes of nocturnal hypoglycaemia. Diabet. Med. 20, 545–551 (2003)     

Effects of recombinant human insulin-like growth factor I and insulin on counterregulation during acute plasma glucose decrements in normal and Type 2 (non-insulin-dependent) diabetic subjects

Summary Insulin-like growth factor I (65 μg/kg) or insulin (0.1 IU/kg) were injected i.v. on two separate occasions in random order in normal and in Type 2 (non-insulin-dependent) diabetic subjects. Insulin-like growth factor I and insulin injection resulted in identical decrements of plasma glucose concentrations after 30 min but in delayed recovery after insulin-like growth factor I as compared to insulin in both groups (p<0.05 insulin-like growth factor I vs insulin). Counterregulatory increases in plasma glucagon, adrenaline, cortisol and growth hormone concentrations after hypoglycaemia (1.9±0.2 mmol/l) in normal subjects were blunted after insulin-like growth factor I administration compared to insulin (p<0.05). Plasma glucose in Type 2 diabetic subjects did not reach hypoglycaemic levels but the acute glucose decrease to 4.5±0.8 mmol/l was associated with significantly lower responses of plasma glucagon and adrenaline but higher cortisol levels after insulin-like growth factor I compared to insulin (p<0.003). Plasma concentrations of non-esterified fatty acids and leucine decreased similarly after insulin-like growth factor I and insulin in both groups. The present results demonstrate that insulin-like growth factor I is capable of mimicking the acute effects of insulin on metabolic substrates (plasma glucose, non-esterified fatty acids, leucine). The decreases of plasma glucose were similar after both peptides in normal and in diabetic subjects who were presumably insulin resistant. Counterregulatory hormone responses to plasma glucose decrements differed, however, between insulin-like growth factor I and insulin and in the diabetic and the control subjects. After insulin-like growth factor I the increases in adrenaline, cortisol, growth hormone and glucagon were blunted in normal subjects despite slightly lower plasma glucose concentrations.     

Rate of fall of blood glucose and physiological responses of counterregulatory hormones,clinical symptoms and cognitive function to hypoglycaemia in Type I diabetes mellitus in the postprandial state

AIMS/HYPOTHESIS: The aim of this study was to establish the effect of a rate of decreasing plasma glucose concentrations on responses to hypoglycaemia, i.e. release of counterregulatory hormones, perception of symptoms, deterioration of cognitive function, and rates of forearm noradrenaline spillover, in the postprandial condition and in the sitting position. METHODS: We studied 11 subjects with Type I (insulin-dependent) diabetes mellitus, twice during clamped insulin-induced hypoglycaemia (2.4 mmol/l) after eating in the sitting position. On one occasion, plasma glucose was decreased at the rate of 0.1+/-0.003 mmol x min(-1) x l(-1) (fast fall), on the other at the rate of 0.03+/-0.001 mmol x min(-1) x l(-1) (slow fall). Subjects underwent a control euglycaemic clamp study as well. RESULTS: In response to fast-fall as compared to slow-fall hypoglycaemia, which was about 30 min longer, cognitive tasks were performed as follows: Trail-Making B, PASAT 2 s, Digit Vigilance Test and Verbal Memory deteriorated more, adrenaline increased less (2.8+/-0.5 vs 3.5+/-0.7 nmol/l, p=0.03), forearm noradrenaline spillover was greater (6.5+/-1.0 vs 5.2+/-0.4 pmol x min(-1) x 100 ml(-1), p=0.04), and symptoms were no different. After recovery from hypoglycaemia, cognitive function was still deteriorated compared to the baseline with no difference between fast and slow-fall hypoglycaemia. The evident response of glucagon to postprandial hypoglycaemia contrasted with the blunted or absent response in the fasting state. CONCLUSION/INTERPRETATION: In the postprandial condition and sitting position, fast-fall hypoglycaemia is more dangerous than slow-fall, because it deteriorates cognitive function more, and activates responses of counterregulatory hormones less than slow-fall hypoglycaemia.     

Taspoglutide,a once‐weekly glucagon‐like peptide 1 analogue,vs. insulin glargine titrated to target in patients with Type 2 diabetes: an open‐label randomized trial

Aims To compare the efficacy and safety of once‐weekly taspoglutide with insulin glargine in patients with advanced Type 2 diabetes failing metformin and sulphonylurea combination therapy. Methods This open‐label, parallel‐group, multi‐centre trial randomized 1049 patients continuing metformin 1:1:1 to taspoglutide 10 mg once weekly, taspoglutide 20 mg once weekly or insulin glargine once daily with forced titration to fasting plasma glucose ≤ 6.1 mmol/l. Sulphonylureas were discontinued before randomization. The primary endpoint was change in HbA_1c after 24 weeks. Results After 24 weeks, least‐square mean changes from baseline in HbA_1c in patients receiving taspoglutide 10 mg [?8 mmol/mol (se 1)] [?0.77% (se 0.05)] or taspoglutide 20 mg [?11 mmol/mol (se 1)] [?0.98% (se 0.05)] were non‐inferior to insulin glargine [?9 mmol/mol (se 1)] [?0.84% (se 0.05)]; treatment difference of 0.07% (95% CI ?0.06 to 0.21) and ?0.14% (95% CI ?0.28 to ?0.01), for taspoglutide 10 and 20 mg, respectively, vs. insulin glargine. Taspoglutide was associated with more adverse events (mainly gastrointestinal) and significantly less hypoglycaemia than insulin glargine. Conclusions Compared with insulin glargine, taspoglutide provided non‐inferior HbA_1c reductions associated with less hypoglycaemia, but more gastrointestinal adverse events.     

Counterregulatory hormones in insulin-treated diabetic patients admitted to an accident and emergency department with hypoglycaemia

The aim of the study was (1) to describe hormone responses in insulin-induced hypoglycaemia and (2) to investigate if a combined treatment with intravenous glucose and intramuscular glucagon (group A) would improve glucose recovery as compared to treatment with intravenous glucose alone (group B). Eighteen adult patients with insulin-treated diabetes mellitus admitted to the Accident and Emergency Department with hypoglycaemia (plasma glucose 1.23 ± 0.15 mmol l⁻¹ on admission) were randomized to one of the above treatments and plasma glucose and counterregulatory hormones were measured before and 30–120 min after treatment. Pre-treatment counterregulatory hormone concentrations were significantly lower than hormone concentrations during induced hypoglycaemia in healthy control subjects but significantly higher than healthy fasting concentrations for plasma adrenaline (p = 0.020), glucagon (p = 0.008), growth hormone (p = 0.011), and cortisol (p<0.00001). Thus, although glucagon and adrenaline responses may be absent when studying Type 1 diabetic patients in the experimental setting, both hormones increase to a significant extent in ‘real-life’ hypoglycaemia in this patient group, although to a lesser degree than might be expected. Plasma glucose did not differ significantly between the two treatments at any time point. Despite access to food, one of four patients in group B and one of five patients in group A had plasma glucose below 4.0 mmol l⁻¹ after 120 min. In conclusion, low yet significantly elevated concentrations of adrenaline and glucagon were found in diabetic patients admitted with severe hypoglycaemia to an Accident and Emergency Department. © 1998 John Wiley & Sons, Ltd.     

Improved glycaemic control with insulin glargine plus insulin lispro: a multicentre, randomized, cross-over trial in people with Type 1 diabetes.

AIMS: To compare blood glucose control using insulin glargine + insulin lispro with that on NPH insulin + unmodified human insulin in adults with Type 1 diabetes managed with a multiple injection regimen. METHODS: In this 32-week, five-centre, two-way cross-over study, people with Type 1 diabetes (n = 56, baseline HbA1c 8.0 +/- 0.8%) were randomized to evening insulin glargine + mealtime insulin lispro or to NPH insulin (once- or twice-daily) + mealtime unmodified human insulin. Each 16-week period concluded with a 24-h inpatient plasma glucose profile. RESULTS: HbA1c was lower with glargine + lispro than with NPH + human insulin [7.5 vs. 8.0%, difference -0.5 (95% CI -0.7, -0.3) %, P < 0.001]. This was confirmed by an 8% lower 24-h plasma glucose area under the curve (AUC) (187 vs. 203 mmol l(-1) h(-1), P = 0.037), a 24% reduction in plasma glucose AUC > 7.0 mmol/l1 (47 vs. 62 mmol l(-1) h(-1), P = 0.017) and a 15% lower post-prandial plasma glucose AUC (75 vs. 88 mmol l(-1) h(-1), P = 0.002). There was no reduction in night-time plasma glucose AUC or increase in plasma glucose area < 3.5 mmol/l. Monthly rate of nocturnal hypoglycaemia was reduced by 44% with glargine + lispro (0.66 vs. 1.18 episodes/month, P < 0.001). CONCLUSIONS: Compared with NPH insulin + unmodified human insulin, the combination of insulin glargine with a rapid-acting insulin analogue as multiple-injection therapy for Type 1 diabetes improves overall glycaemic control as assessed by HbA1c and 24-h plasma glucose monitoring to a clinically significant degree, together with a reduction in nocturnal hypoglycaemia.     

A Comparative Study of Responses to Acute Hypoglycaemia Induced by Human and Porcine Insulins in Patients with Type 1 Diabetes

The effects of human and porcine insulins on the symptomatic, physiological, and counterregulatory hormonal responses to acute hypoglycaemia were compared in 40 patients with Type 1 diabetes, 20 of whom were newly diagnosed while 20 had been treated for between 5 and 20 years. In a double-blind, cross-over trial all patients were treated with human or porcine insulin, in random order, for two consecutive 3-month periods. At the end of each treatment period they were subjected to an acute episode of experimental hypoglycaemia induced by a continuous intravenous infusion (2.0 mU kg⁻¹ min⁻¹) of the same insulin species. Haemodynamic, sweating, and tremor responses were measured during both studies, symptom scores were recorded and the arterialized plasma glucose thresholds for autonomic activation and the onset of subjective symptoms were identified. In all patients the glycaemic thresholds for the initiation of the autonomic physiological responses to hypoglycaemia and the onset of the symptomatic response were concurrent and did not differ with insulin species (plasma glucose 1.94 vs 1.96 mmol l⁻¹, human vs porcine studies). The onset, temporal pattern, nature, and magnitude of the physiological responses (sweating, heart rate, blood pressure, and tremor) during acute experimental hypoglycaemia were also identical with each insulin species. The magnitude and temporal pattern of the response of counterregulatory hormones (adrenaline, noradrenaline, glucagon, ACTH, and GH) to hypoglycaemia as induced by human and porcine insulins were indistinguishable, as were the total and individual scores of autonomic and neuroglycopenic symptoms. In conclusion, in patients who had newly diagnosed and intermediate duration (5–20 years) of diabetes, the symptomatic, physiological, and counterregulatory hormonal responses to acute insulin-induced hypoglycaemia did not differ between human and porcine insulins, and the plasma glucose thresholds at which the symptomatic and autonomic responses were initiated were identical with both insulin species. This study does not support the hypothesis that treatment with human insulin modifies the symptomatic, physiological, and counterregulatory hormonal responses to acute hypoglycaemia.     

Counterregulatory responses to hypoglycemia in patients with glucokinase gene mutations

The glucokinase gene is expressed not only in pancreatic B cells and in the liver, but also in pancreatic alpha cells, and in some cells of the central nervous system. A decreased glucokinase activity in the latter cell types may interfere with counterregulatory responses to hypoglycemia. In order to assess functional consequences of glucokinase mutations, counterregulatory hormones secretion and glucose production (6,6(- 2) H glucose) were monitored during an hyperinsulinemic clamp at about 2.4 pmol.kg(- 1).min(- 1) insulin with progressive hypoglycemia in 7 maturity onset diabetes of the young (MODY) type 2 patients, 5 patients with type 2 diabetes, and 13 healthy subjects. Basal glucose concentrations were significantly higher in MODY2 patients (7.6 +/- 0.4 mmol.l(- 1) ) and type 2 diabetic patients (12.4 +/- 2.3 mmol.l(- 1) ) than in healthy subjects (5.3 +/- 0.1 mmol.l(- 1), p<0.01) but counterregulatory hormones concentrations were identical. Insulin-mediated glucose disposal and suppression of endogenous glucose production at euglycemia were unchanged in MODY2 patients, but were blunted in type 2 diabetes. During progressive hypoglycemia, the glycemic thresholds of MODY2 patients for increasing glucose production (5.0 +/- 0.4 mmol.l(- 1) ) and for glucagon stimulation (4.5 +/- 0.4 mmol. l(- 1) ) were higher than those of healthy subjects and type 2 diabetic patients (3.9 +/- 0.1 and 4.1 +/- 0.1 mmol.l(- 1) respectively for glucose production and 3.7 +/- 0.1 and 3.5 +/- 0.1 mmol.l(- 1) for glucagon stimulation, p <0.02 in both cases). These results indicate that counterregulatory responses to hypoglycemia are activated at a higher plasma glucose concentration in MODY2 patients. This may be secondary to decreased glucokinase activity in hypothalamic neuronal cells, or to alterations of glucose sensing in pancreatic alpha cells and liver cells.     

Add‐on treatment with intermediate‐acting insulin versus sliding‐scale insulin for patients with type 2 diabetes or insulin resistance during cyclic glucocorticoid‐containing antineoplastic chemotherapy: a randomized crossover study

The aim of this study was to compare the effectiveness and safety of intermediate‐acting insulin (IMI) titrated on body weight and glucocorticoid dose with that of short‐acting sliding‐scale insulin (SSI) in patients on recurrent high‐dose glucocorticoid‐containing chemotherapy. We enrolled 26 patients with type 2 diabetes mellitus or random blood glucose level >12 mmol/l in a previous cycle of chemotherapy in a randomized crossover study. In two consecutive cycles of glucocorticoid‐containing chemotherapy, participants were treated with either IMI or SSI, as add‐on to routine diabetes medication. We compared time spent in target range (3.9–10 mmol/l), measured by continuous glucose monitoring (CGM), and the occurrence of hypoglycaemia. IMI resulted in a higher proportion of glucose values within target range than SSI (34.4 vs 20.9%; p < 0.001). There were no severe or symptomatic hypoglycaemic events. Two participants in each group had a subclinical hypoglycaemia detected only by CGM. Once‐daily IMI resulted in better glycaemic control than SSI in patients with glucocorticoid‐induced hyperglycaemia during chemotherapy. Safety was not compromised as the incidence of hypoglycaemia was low and not different between both regimens.     

Counterregulatory hormonal responses to hypoglycaemia in Type 1 (insulin-dependent) diabetes: evidence for diminished hypothalamic-pituitary hormonal secretion

Summary Acute insulin-induced hypoglycaemia in humans provokes autonomic neural activation and counterregulatory hormonal secretion mediated in part via hypothalamic stimulation. Many patients with Type 1 (insulin-dependent) diabetes have acquired deficiencies of counterregulatory hormonal release following hypoglycaemia. To study the integrity of the hypothalamic-pituitary and the sympatho-adrenal systems, the responses of pituitary hormones, beta-endorphin, glucagon and adrenaline to acute insulin-induced hypoglycaemia (0.2 units/kg) were examined in 16 patients with Type 1 diabetes who did not have autonomic neuropathy. To examine the effect of duration of diabetes these patients were subdivided into two groups (Group 1: 8 patients < 5 years duration; Group 2 8 patients>15 years duration) and were compared with 8 normal volunteers (Group 3). The severity and time of onset of hypoglycaemia were similar in all 3 groups, but mean blood glucose recovery was slower in the diabetic groups (p<0.01). The mean responses of glucagon, adrenaline, adrenocorticotrophic hormone, prolactin and beta-endorphin were similar in all 3 groups, but the mean responses of growth hormone were lower in both diabetic groups than in the normal group (p<0.05). The mean increments of glucagon and adrenaline in the diabetic groups were lower than the normal group, but these differences did not achieve significance; glucagon secretion was preserved in several diabetic patients irrespective of duration of disease. Various hormonal responses to hypoglycaemia were absent or diminished in individual diabetic patients, and multiple hormonal deficiencies could be implicated in delaying blood glucose recovery. The demonstration of subnormal secretion of adrenaline and pituitary hormones following hypoglycaemia in individual patients supports the concept that central (hypothalamic) activation of counterregulation may be diminished in Type 1 diabetes.     

Brain function rescue effect of lactate following hypoglycaemia is not an adaptation process in both normal and Type I diabetic subjects

Aims/hypothesis. We have previously shown that lactate protects brain function during insulin-induced hypoglycaemia. An adaptation process could, however, not be excluded because the blood lactate increase preceded hypoglycaemia.¶Methods. We studied seven healthy volunteers and seven patients with Type I (insulin-dependent) diabetes mellitus with a hyperinsulinaemic (1.5 mU · kg^–1· min^–1) stepwise hypoglycaemic clamp (4.8 to 3.6, 3.0 and 2.8 mmo/l) with and without Na-lactate infusion (30 μmol · kg^–1· min^–1) given after initiation of hypoglycaemic symptoms.¶Results. The glucose threshold for epinephrine response was similar (control subjects 3.2 ± 0.1 vs 3.2 ± 0.1, diabetic patients = 3.5 ± 0.1 vs 3.5 ± 0.1 mmol/l) in both studies. The magnitude of the response was, however, blunted by lactate infusion (AUC; control subjects 65 ± 28 vs 314 ± 55 nmol/l/180 min, zenith = 2.6 ± 0.5 vs 4.8 ± 0.7 nmol/l, p < 0.05; diabetic patients = 102 ± 14 vs 205 ± 40 nmol/l/180 min, zenith = 1.4 ± 0.4 vs 3.2 ± 0.3 nmol/l, p < 0.01). The glucose threshold for symptoms was also similar (C = autonomic 3.0 ± 0.1 vs 3.0 ± 0.1, neuroglycopenic = 2.8 ± 0.1 vs 2.9 ± 0.1 mmol/l, D = autonomic 3.2 ± 0.1 vs 3.2 ± 0.1, neuroglycopenic 3.1 ± 0.1 vs 3.2 ± 0.1 mmol/l) but peak responses were significantly attenuated by lactate (score at 160 min C = 2.6 ± 1 vs 8.8 ± 1, and 0.4 ± 0.4 vs 4.8 ± 1, respectively; p = 0.02–0.01, D = 1.3 ± 0.5 vs 6.3 ± 1.7, and 2.3 ± 0.6 vs 5.7 ± 1.1 p = 0.07–0.02). Cognitive function deteriorated in both studies at similar glucose thresholds (C = 3.1 ± 0.1 vs 3.0 ± 0.1, D = 3.2 ± 0.1 vs 3.3 ± 0.2 mmol/l). Although in normal subjects a much smaller impairment was observed with lactate infusion (Δ four-choice reaction time at 160 min = 22 ± 12 vs 77 ± 31 ms; p = 0.02), in Type I diabetic patients lactate infusion was associated with an improvement in cognitive dysfunction (0.2 ± 0.4 vs –38 ± 0.2 Δ ms, p = 0.0001).¶Conclusion/interpretation. A blood lactate increase after the development of hypoglycaemic symptoms reduces counterregulatory and symptomatic responses to insulin-induced hypoglycaemia and favours brain function rescue both in normal and diabetic subjects. These findings confirm that lactate is an alternative substrate to glucose for cerebral metabolism under hypoglycaemic conditions. [Diabetologia (2000) 43: 733–741]