Magnus Kollind

Arterial, arterialized venous, venous and capillary blood glucose measurements in normal man during hyperinsulinaemic euglycaemia and hypoglycaemia

SummaryThe purpose of this study was to evaluate the effectiveness of the warm-air box method on the arterialization of venous blood during euglycaemia and hypoglycaemia. Six healthy male volunteers were studied using an i.v. infusion of insulin (144 mU·kg−1·h−1). Arterial blood glucose was clamped at the baseline level for the first 30 min and subsequently reduced to 3.2 and to 2.5 mmol/l for 20 min. At each stage, including prior to insulin infusion, arterial, arterialized venous (heating the hand in a warm-air box set to 55–60°C), venous and capillary blood samples were taken simultaneously for analyses of blood glucose and oxygen saturation (not for capillary blood). The oxygen saturations in arterialized blood were approximately 3% below the arterial values. The arterial-arterialized difference of blood glucose was about 0.1 mmol/l (the 95% confidence interval: from −0.19 to 0.41 mmol/l), which tended to correlate with the difference in oxygen saturations between the arterial and arterialized blood samples (r=0.25, p=0.08). During the test the forearm venous blood oxygen saturation increased by 9% and the arteriovenous difference in blood glucose ranged from 0.2 to 0.5 mmol/l which correlated significantly with the difference in oxygen saturations (r=0.48, p<0.001). Capillary glucose was similar to the arterialized value. Rectal temperature was stable during the experiment. We conclude that the heated hand technique using the warm-air box sufficiently arterializes venous blood so that the glucose measurement in the arterialized blood provides a reasonable estimate of the arterial value and that the venous blood from the contralateral forearm is also markedly arterialized, probably reflecting a vasodilator effect of heating.

Acute mental stress impairs insulin sensitivity in IDDM patients

SummaryThe effect of acute mental stress on insulin sensitivity was evaluated in ten IDDM patients, studied on two occasions (test day and control day) in random order and separated by a period of 1–3 weeks. Mental stress was evoked by a modified filmed version of Stroops CWT for 20 min. On the control day, the patients were resting quietly during the corresponding period. Insulin sensitivity was estimated by an insulin (0.4 mU · kg−1 · min−1)-glucose (4.5 mg · kg−1 · min−1)-infusion test (IGIT) for 6.5 h. Mental stress evoked significant responses for adrenaline, cortisol and GH, their respective peak values being 0.27 ± 0.05 nmol/l, 426 ± 27 nmol/l and 7.6 ± 1.8 μg/l, as well as increases in systolic and diastolic blood pressure and pulse rate The steady-state blood glucose levels, i.e. the mean blood glucose levels 3–6.5 h after the start of the IGIT, were significantly higher after stress, compared with those on the control day, 10.6 ± 1.5 vs 8.7 ± 1.4 mmol/l, p = 0.01, demonstrating impairment of the insulin sensitivity by mental stress. It is concluded that acute mental stress induces a state of insulin resistance in IDDM patients, which can be demonstrated by an IGIT to appear 1 h after maximal stress and to last more than 5 h.

Inhibitory Effect of Circulating Insulin on Glucagon Secretion During Hypoglycemia in Type I Diabetic Patients

Objective –To clarify whether the circulating insulin level influences hormonal responses, glucagon secretion in particular, during hypoglycemia in patients with insulin-dependent (type I) diabetes. Research Design and Methods –Nine type I diabetic patients were studied. During two separate experiments, hypoglycemia was induced by low-dose (244 pmol.kg−1.h−1) and high-dose (1034 pmol.kg−1.h−1) intravenous insulin infusions for 180 min in each case. The arterial blood glucose level was directly monitored every 1.5 min, and glucose was infused in the high-dose test to clamp the arterial blood glucose level to be identical as in the low-dose test. Results –Despite the fact that the plasma insulin level was four times higher in the high-dose than in the low-dose test (740 ± 50 vs. 180 ± 14 pM), a close to identical arterial hypoglycemia of ∼ 3.3 mM was obtained in the two experiments. During hypoglycemia, a significant rise of the plasma glucagon level was found only in the low-dose test (188 ± 29 vs. 237 ± 37 ng/L, P < 0.05), and the incremental area under the glucagon curve was significantly greater in the low-dose than in the high-dose test (140 ± 19 vs. −22.7 ± 34 ng/L.h−1, P < 0.005). The responses of plasma epinephrine, norepinephrine, growth hormone, pancreatic polypeptide, and somatostatin were similar in both tests and, consequently, were not significantly modified by the circulating insulin level. Conclusions –This study demonstrates that, in type I diabetic patients, the glucagon response to hypoglycemia is suppressed by a high level of circulating insulin within the physiological range. Our findings may help to explain the impairment of glucagon secretion during hypoglycemia frequently seen in these patients.

Six months of diazoxide treatment at bedtime in newly diagnosed subjects with type 1 diabetes does not influence parameters of β-cell function and autoimmunity, but improves glycemic control.

OBJECTIVE Continuous β-cell rest with diazoxide preserves residual endogenous insulin production in type 1 diabetes. However, side effects have hampered therapeutic usefulness. In a double-blind study, we tested whether lower, intermittent dosing of diazoxide had beneficial effects on insulin production, metabolic control, and autoimmunity markers in the absence of side effects. RESEARCH DESIGN AND METHODS Forty-one newly diagnosed type 1 diabetic patients were randomized to 6 months of treatment with placebo or 100 mg diazoxide at bedtime. A1C, C-peptide (fasting and glucagon stimulated), and FoxP3+ regulatory T-cells (Tregs) were measured. Patients were followed for 6 months after intervention. RESULTS Of six dropouts, three were due to perceived side effects; one subject in the diazoxide group experienced rash, another dizziness, and one in the placebo group sleep disturbance. Adverse effects in others were absent. Diazoxide treatment reduced A1C from 8.6% at baseline to 6.0% at 6 months and 6.5% at 12 months. Corresponding A1C value in the placebo arm were 8.3, 7.3, and 7.5% (P < 0.05 for stronger reduction in the diazoxide group). Fasting and stimulated C-peptide decreased during 12 months similarly in both arms (mean −0.30 and −0.18 nmol/l in the diazoxide arm and −0.08 and −0.09 nmol/l in the placebo arm). The proportion of Tregs was similar in both arms and remained stable during intervention but was significantly lower compared with nondiabetic subjects. CONCLUSIONS Six months of low-dose diazoxide was without side effects and did not measurably affect insulin production but was associated with improved metabolic control.

Transient insulin resistance following infusion of adrenaline in Type 1 (insulin-dependent) diabetes mellitus

SummaryInsulin resistance was assessed after an intravenous infusion of adrenaline (50 ng·kg−1·min−1) or saline (control study) given between 08.00 and 08.30 hours in nine patients with Type 1 (insulin-dependent) diabetes mellitus. The blood glucose level during a somatostatin (100μg/h)-insulin (0.4mU·kg−1·min−1)-glucose (4.5 mg·kg−1·-min−1)-infusion-test performed between 1030 and 14.30 hours served as an indicator of the total body insulin resistance. Blood glucose was maintained around 7 mmol/l between 08.00 and 10.30 hours by a constant infusion of regular insulin (0.57 mU·kg−1· min−1) and a variable infusion of a 20% glucose solution. The infusion of adrenaline raised plasma adrenaline to 2.7±0.3 nmol/l (mean±SEM) at the end of the infusion; thereafter it returned to its basal level within 30 min. The plasma levels of free insulin, glucagon, cortisol and growth hormone were similar in the adrenaline and the control studies from 08.00 to 14.30 hours. In comparison with the control study the infusion of adrenaline decreased the need for intravenous glucose significantly over the initial 2 h. Furthermore, during the somatostatin-insulin-glucose infusion test the blood glucose rose significantly (p<0.05) over the initial 2h; thereafter no significant differences between the two studies were seen. It is concluded that a short term infusion of adrenaline, resembling the adrenergic hormone response to hypoglycaemia, induces a diabetogenic effect which subsides within 6 h after omission of the adrenaline infusion.

Comment to: Hoi-Hansen T, Pedersen-Bjergaard U, Thorsteinsson B (2005) The Somogyi phenomenon revisited using continuous glucose monitoring in daily life. Diabetologia 48:2437–2438

To the Editor: Using a continuous glucose monitoring system (CGMS), Hoi-Hansen and coworkers [1] recently rejected the existence of the Somogyi phenomenon, having analysed valid glucose data obtained in a large group of type 1 diabetic patients, representing 594 nights. We believe this is an important paper since, in our experience, health care professionals frequently believe that the Somogyi phenomenon exists. Because it remains an important issue, we investigated this concept further. The Somogyi phenomenon was first recognised in 1949, when Dr Michael Somogyi presented a paper at the American Chemical Society meeting in Atlantic City (NJ, USA) indicating that many diabetic patients were receiving such large doses of insulin that they were ‘actually victims of chronic insulin poisoning’. He hypothesised that insulininduced hypoglycaemia at night generated the release of counter-regulatory hormones, which, in turn, caused insulin resistance and hyperglycaemia. Since at that time the methodologies required for measuring blood levels of glucose and counter-regulatory hormones had not been developed, it should be noted that his hypothesis was based on the assessment of urinary glucose excretions alone. M. Somogyi published over 70 papers on various aspects of clinical chemistry, and his last major article was published in the American Journal of Medicine in 1959, as outlined in the elegant review of his scientific contributions, written by H. Walker Jr and published in 1972 [2]. In his paper, M. Somogyi summarised his ideas in the phrase ‘hypoglycaemia begets hyperglycaemia’, which became known as the Somogyi effect. In their article, Hoi-Hansen and coworkers cite the wellknown papers by Gale et al. [3] and by other groups, referring to these investigations as experimental studies that provide evidence against the existence of the Somogyi phenomenon. Going through these papers, we believe, however, that it would be more appropriate to address these studies as observational rather than experimental, and would like to point out that although experimental studies have documented that nocturnal hypoglycaemia induces a state of insulin resistance in type 1 diabetic patients [4], this causes post-breakfast rather than fasting hyperglycaemia [5]. Given that counter-regulatory hormones released by hypoglycaemia would mediate the Somogyi effect, we have to consider the mode of action of these hormones, particularly growth hormone, which is known to induce insulin resistance after a lag period of several hours [6]. In our opinion, the question of whether an alteration in insulin sensitivity, evoked by the release of growth hormone, would generate a glycaemic effect prominent enough to be detected in clinical practice in diabetic patients still remains to be fully elucidated. A few studies in which glucose profiles after hypoglycaemia were monitored beyond fasting values have been presented [7, 8].These observational studies were unable to convincingly detect significant hyperglycaemic effects of nocturnal hypoglycaemia during the following daytime period. These observational studies, which were conducted over 15 years ago, were unable to detect significant hyperglycaemic effects during the day after nocturnal hypoglycaemia. However, nocturnal glucose levels were not monitored continuously (blood samples were taken every several hours), which means that episodes of undetected hypoglycaemia may be a confounding factor. I. Iseda . P. E. Lins . U. Adamson . M. Kollind Department of Medicine, Karolinska Institute Danderyd Hospital, Danderyd, Sweden