["This is only an old man's sugar disease!"].
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Aged↗
Biomedical subjects
H Beck-Nielsen
Publications and source records attributed to H Beck-Nielsen.
[Non-insulin-dependent diabetes mellitus. Diagnosis and treatment. An interpretation].
There are approximately 100,000 non-insulin-dependent diabetics in the Danish population and the incidence appears to be increasing. As the disease is complicated by a series of arteriosclerotic manifestations together with hypertension and eye changes, it presents great problems in the primary and also in the secondary sector. The Danish Association for Internal Medicine has, on this basis, prepared an explanatory report with the main object of establishing guidelines for treatment of the disease both medically and by organisation. The report contains a review of the patho-physiological conditions with emphasis on resistance to insulin and the basic cellular defect. The connections with arteriosclerosis and hypertension are also emphasized. The significance of the diet in the treatment of the condition is also emphasized as approximately 80% of the patients are overweight. Guidelines for treatment with sulphonurea, biguanides and insulin are presented. In order to provide optimal treatment and control of non-insulin-dependent diabetics and to provide them a better quality of life closer cooperation between general practitioners and diabetic clinics is recommended. In particular, it appears to be desirable to involve diabetic clinics at the commencement of the disease when the need for training is great.
Adult↗
On the determination of basal glucose production rate in patients with type 2 (non-insulin-dependent) diabetes mellitus using primed-continuous 3-3H-glucose infusion.
UNLABELLED: Using primed-continuous 3-3H-glucose infusion, basal glucose production rate has been reported to be 140% higher than normal or almost normal in hyperglycaemic patients with Type 2 (non-insulin-dependent) diabetes mellitus. To determine whether these markedly different results could be due to the mode of priming: fixed or adjusted, or the mode of calculation: steady state or non-steady state equations, we studied 11 patients with Type 2 diabetes (fasting plasma glucose 8-20 mmol/l). For 6 h 3-3H-glucose (0.40 microCi/min) was infused preceded by a priming dose of 40 microCi (fixed priming), or 40 microCi.plasma glucose (mmol/l).5(-1) (adjusted priming). In diabetic patients the plasma glucose concentration was not constant but declined 0.52 +/- 0.07 mmol.l-1.h-1. Furthermore, the rate of fall was correlated to the fasting plasma glucose concentration (r = 0.90, p less than 0.01). Thus, the fasting state was not a steady state condition. Using adjusted priming a constant tracer steady state level was obtained within 60 min. In contrast, using fixed priming tracer steady state was not reached within 6 h. The initial tracer level was far below, and increased in time towards the steady state level observed after adjusted priming. Consequently, using Steele's equations after fixed priming, glucose production rates calculated after 90-120 min were overestimated in proportion to fasting hyperglycaemia. IN CONCLUSION: The fasting state in patients with Type 2 diabetes is not a steady state condition. Adjusted priming seems most appropriate in Type 2 diabetes.(ABSTRACT TRUNCATED AT 250 WORDS)
Blood Glucose↗
Expression of insulin regulatable glucose transporters in skeletal muscle from type 2 (non-insulin-dependent) diabetic patients.
A prominent feature of Type 2 (non-insulin-dependent) diabetes mellitus is the inability of insulin to appropriately increase the transport of glucose into target tissue. In adipocytes from individuals with Type 2 diabetes, insulin resistance has been shown to be associated with a depletion of glucose transporters. Similarly, streptozotocin induced diabetes causes a diminished expression of the insulin regulatable glucose transporter in rat adipocytes. The expression of this glucose transporter isoform has not yet been investigated in muscle tissue from patients with Type 2 diabetes. We have measured the content of the insulin regulatable glucose transporter in a vesicular fraction isolated from muscle biopsies from fasting individuals with Type 2 diabetes and control subjects, and we found that the number of the insulin regulatable glucose transporters expressed in skeletal muscle was unaffected by Type 2 diabetes (0.208 vs 0.205, arbitrary units, p greater than 0.5, control subjects and diabetic patients). Thus, the decreased glucose disposal in Type 2 diabetes is not associated with a diminished number of insulin regulatable glucose transporters.
Animals↗
Impairment of glucose tolerance: mechanism of action and impact on the cardiovascular system.
Macrovascular disease, especially coronary heart diseases, have been found to be linked to glucose intolerance. Insulin resistance in respect to glucose uptake in peripheral tissues seems to play an important role in the development of glucose intolerance, since subjects with coronary heart disease mainly are hyperinsulinemic. Insulin resistance may induce not only glucose intolerance but also hypertension, obesity, and dyslipoproteinemia (high very low-density lipoprotein and low high-density lipoprotein values), all variables that add to the risk of coronary heart disease. On the basis of these findings, a new syndrome has been postulated-syndrome X. This syndrome may be caused by inherited insulin resistance in skeletal muscles, and secondary to that arterial hypertension, obesity, and dyslipoproteinemia may develop. Insulin resistance in noninsulin-dependent diabetic persons and in hypertensive subjects is located in skeletal muscles, where insulin's ability to promote nonoxidative glucose metabolism is reduced. The key enzyme in this pathway, glycogen synthase, is proposed as the causal defect responsible for the insulin resistance state, at least in noninsulin-dependent diabetic patients. The pill (sex steroids) may induce a clinical situation that is similar to syndrome X. However, it is important to emphasize that many more studies are needed to substantiate these hypothetical mechanisms behind coronary heart disease.
Blood Glucose↗
Concentration-response relationship in imipramine treatment of diabetic neuropathy symptoms.
A single-blind imipramine dose titration study was conducted in 15 diabetic patients with neuropathy symptoms. The effect of treatment was evaluated by use of visual analog scales. Imipramine doses were individually adjusted until doses yielded plasma concentrations of imipramine plus desipramine that were well above 400 nmol/L or until all neuropathy symptoms had vanished. In all except one patient, there was marked relief of symptoms. In the responding patients (n = 14), much of the effect occurred at plasma levels of imipramine plus desipramine below 100 nmol/L, but a considerable interindividual variation was observed. Concentrations above 400 to 500 nmol/L were required to ensure maximal effect in all patients, and we did not find any indication of a decreased effect at high drug levels. The dose-dependent kinetics of imipramine was confirmed, and dose increments should therefore be carried out in small steps and preferably with monitoring of drug levels.
Adult↗
Clomipramine vs desipramine vs placebo in the treatment of diabetic neuropathy symptoms. A double-blind cross-over study.
1. The effect of clomipramine and desipramine on diabetic neuropathy symptoms was examined in a double-blind, randomised, placebo controlled, cross-over study for 2 + 2 + 2 weeks. Drug doses were adjusted according to the sparteine phenotype, i.e. extensive metabolisers were treated with 75 mg clomipramine day-1 and 200 mg desipramine day-1 whereas poor metabolisers were treated with 50 mg day-1 of both drugs. Nineteen patients completed the study. 2. Plasma concentration of clomipramine plus desmethylclomipramine was 70-510 nM in extensive metabolisers, vs 590 and 750 nM in two poor metabolisers. Desipramine levels were 130-910 nM, vs 860 and 880 nM. 3. Both clomipramine and desipramine significantly reduced the symptoms of neuropathy as measured by observer- and self rating in comparison with placebo. Clomipramine tended to be more efficacious than desipramine. Patients with a weak or absent response on clomipramine had lower plasma concentrations (clomipramine plus desmethyl-clomipramine less than 200 nM) than patients with a better response. For desipramine a relationship between plasma concentration and effect was not established. 4. Side effect ratings did not differ for clomipramine and desipramine and on both drugs three patients withdrew due to side effects. 5. Compared with earlier results obtained with imipramine dosed on the basis of plasma level monitoring, clomipramine and desipramine on fixed doses appeared less efficacious whereas the side effect profiles were the same. At least for clomipramine, appropriate dose adjustment on the basis of plasma level monitoring may increase the efficacy.
Adult↗
Intramuscular versus subcutaneous injection of unmodified insulin: consequences for blood glucose control in patients with type 1 diabetes mellitus.
Using the perpendicular injection technique lean diabetic patients may often inject insulin intramuscularly (IM). Guided by ultrasound measurements of the subcutaneous (SC) thickness of the thigh, the aim of the present study was to re-evaluate the absorption kinetics of unmodified insulin from IM and SC injection sites and to evaluate the consequences of IM injection of unmodified insulin for blood glucose control in Type 1 diabetic patients. T50% values (time until 50% of the injected insulin is absorbed from the injection site) of SC injected, radioactively labelled, human unmodified insulin (125I-Actrapid) were 338 +/- 13 (+/- SE) min, 289 +/- 27 min, and 287 +/- 27 min during rest, light physical activity, and strenuous exercise, respectively. Intramuscularly injected unmodified insulin was absorbed faster, T50% 232 +/- 20 min, 113 +/- 13 min, and 112 +/- 5 min during the same levels of physical activity in the same order. When unmodified insulin (Actrapid) was given IM 30 min before breakfast, lunch, and dinner together with intermediate-acting insulin (Protaphane) SC at 2200 h, a more physiological profile of plasma free insulin and a more stable blood glucose profile was obtained than with SC administration into the thigh. The coefficient of variation of blood glucose concentration during the study (3 days each route) was lower with IM than with SC injection of unmodified insulin (33 +/- 4 vs 43 +/- 3%, p less than 0.01). No difference in frequency of hypoglycaemic attacks was found and patients claimed that IM injection was no more painful than SC injection. These data suggest that IM injection of soluble insulin into the thigh is beneficial.
Adipose Tissue↗
Variation in absorption of NPH insulin due to intramuscular injection.
To evaluate the importance of accidental intramuscular injection of NPH insulin, we measured disappearance rates of 125I-labeled NPH insulin (Protaphane) from subcutaneous and intramuscular injection sites in the thighs of 11 insulin-dependent diabetes mellitus patients. Both subcutaneous and intramuscular absorption rates were measured four times in each patient. NPH insulin was absorbed much faster when given intramuscularly than when given subcutaneously (T50% = 5.3 vs. 10.3 h, P less than 0.0001). The intrapatient (day-to-day) coefficient of variation (C.V.) of T50% values (C.V. T50%) for subcutaneously injected NPH insulin in this study, where all injections were guided by ultrasound determination of the subcutaneous fat layer, was 18.4%. Intrapatient variation of absorption was significantly lower for subcutaneously than intramuscularly injected NPH insulin (C.V. T50% = 18.4 vs. 29.8%, P less than 0.01) and was also lower than interpatient variation for subcutaneously injected insulin (C.V. T50% = 18.4 vs. 50%, P less than 0.0001). The faster absorption rate and shorter duration of action, together with the higher day-to-day variation in absorption, led us to conclude that intramuscular injection of NPH insulin should be avoided.
Absorption↗
Acute actions of sulfonylurea drugs during long-term treatment of NIDDM.
The acute effect of sulfonylurea drugs during long-term treatment was evaluated in two separate studies. In the first study, the levels of plasma glucose, insulin, and C-peptide were measured after intake of 10 mg glyburide alone or together with a standardized mixed meal in 10 non-insulin-dependent diabetes mellitus (NIDDM) patients treated with 10-20 mg glyburide/day for greater than 2 yr. There was no acute effect of glyburide on the insulin and C-peptide responses to the meal or during continued fasting, indicating the absence of an acute insulinotropic action of glyburide during chronic treatment. The glucose increase after the meal was also unchanged, but a significant glucose reduction was found after glyburide intake during continued fasting, suggesting a sustained acute extrapancreatic (hepatic) effect. In the second study, the diurnal glycemic excursions in 8 NIDDM patients chronically and continuously (24 h/day) exposed to glipizide (2.5-7.5 mg 3 times/day) were similar when the drug was taken 30 min before each of the three main meals and when taken immediately before the meals. It is concluded that there is no acute insulinotropic action of sulfonylurea drugs during chronic continuous exposure, whereas an acute extrapancreatic action may prevail. During such exposure, there seems to be no clinical benefit in taking a sulfonylurea 30 min before rather than at the start of a meal.
Aged↗
Effect of near normoglycemia for 5 years on progression of early diabetic retinopathy and renal involvement.
The effect of strict metabolic control for 5 years on renal function and retinal morphology was estimated in 24 insulin-dependent diabetic individuals (age 29 +/- 8 years, diabetes duration 10 +/- 6 years) with albustix negative urine and minimal or no background retinopathy before the study. They were randomized to conventional insulin treatment (CIT) or continuous subcutaneous insulin infusion (CSII) with a portable pump. During CSII treatment the metabolic status was significantly improved. HbA1c fell from 8.9 +/- 2.0 to 7.4 +/- 1.3% (p less than 0.01) whereas HbA1c was unchanged during CIT treatment. The mean value of urinary albumin excretion (UAE) was not statistically significantly changed (from 12 +/- 10 mg/24 h to 13 +/- 5 mg/24 h in CSII patients and from 14 +/- 12 to 11 +/- 6 mg/24 h in CIT patients (p greater than 0.1). On the other hand, the elevated GFR values were significantly reduced in both CSII and CIT patients, 129 +/- 17 to 120 +/- 9 and 129 +/- 18 to 119 +/- 12 ml/min.1,73m2, respectively (p less than 0.05). Both the number of microaneurysms, haemorrhages and exudates tended to increase mor in CIT patients than in CSII patients during the 5 year study period, but the differences did not reach statistically significance (p greater than 0.1). Pump treatment did not induce proliferations or "cotton wool" exudates. We conclude that no statistically significantly differences between GFR values, UAE rates, and progression of background retinopathy was observed between normoalbuminuric IDDM patients treated for 5 years with CIT and CSII, respectively. However, due to the size of the material a type II error must be taken into consideration.
Adult↗
Insulin resistance in skeletal muscles of patients with diabetes mellitus.
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Diabetes Mellitus↗
Insulin resistance: a scientific and clinical challenge.
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Diabetes Mellitus↗
Effects of insulin on kidney function and sodium excretion in healthy subjects.
Insulin action on kidney function was evaluated in 8 healthy subjects, (mean age 27 years) using the euglycaemic clamp technique. Insulin was infused at rates of 0, 20 and 40 mU.min-1.m-2 over consecutive periods of 120 min resulting in plasma insulin concentrations of 8 +/- 2, 29 +/- 7 and 66 +/- 14 mU/l. The renal clearance of 51Cr-EDTA, lithium, sodium and potassium was determined during the last 90 min of each period. Sodium clearance declined with increasing plasma insulin concentrations (1.3 +/- 0.4, 1.0 +/- 0.3 and 0.5 +/- 0.2 ml.min-1.1.73 m-2, p less than 0.001), while glomerular filtration rate (108 +/- 21, 104 +/- 21 and 108 +/- 20 ml.min-1. 1.73 m-2) and lithium clearance (a marker of fluid flow rate from the proximal tubules) 29 +/- 5, 29 +/- 4 and 30 +/- 4 ml.min-1.1.73 m-2) remained unchanged. Calculated proximal tubular reabsorption of sodium and water was unchanged, while calculated distal fractional sodium reabsorption increased (95.5 +/- 1.5, 96.4 +/- 1.2 and 98.1 +/- 0.7%, p less than 0.001). Potassium clearance and plasma potassium concentration declined, whereas plasma aldosterone and plasma renin concentrations were unchanged. In conclusion, elevation of plasma insulin concentration within the physiological range has a marked antinatriuretic action. This effect is located distally to the proximal renal tubules.
Adult↗
Antithrombin III activity, von Willebrand factor antigen and platelet function in young diabetic patients treated with multiple insulin injections versus insulin pump treatment.
In a prospective study with cross-over design 20 patients with insulin-dependent diabetes mellitus of more than 2 years duration were treated for 6 months with continuous subcutaneous insulin infusion (CSII) and multiple insulin injections (MII). Metabolic control, platelet aggregability, thromboxane B2 levels in serum and plasma as well as antithrombin III (ATIII) activity and von Willebrand factor antigen were evaluated. A good metabolic control was obtained by both intensified regimens. No difference could be demonstrated between either platelet function tests or serum level of von Willebrand factor antigen during treatment with CSII and MII. However, the plasma level of ATIII activity was significantly higher (P less than 0.01) during MII treatment as compared to CSII treatment. There was no correlation between ATIII activity and daily insulin requirement or serum fructosamine. In conclusion, long-term metabolic control with MII has a favourable effect on ATIII activity in plasma. This may be important for a delay in onset and progression of diabetic vascular complications.
Adult↗
The effects of metformin on adipocyte insulin action and metabolic control in obese subjects with type 2 diabetes.
To investigate the mechanisms of action of metformin, insulin receptor binding and the activity of several insulin-controlled metabolic pathways were measured in adipocytes taken from 10 obese Type 2 diabetic patients treated for 4 weeks with either metformin (0.5 g x 3 daily) or matching placebo using a double-blind crossover design. Metformin therapy was associated with a significant fall in serum fructosamine levels (3.1 +/- 0.4 vs 2.8 +/- 0.4 mmol l-1, p less than 0.02) as well as fasting (10.8 +/- 2.4 vs 9.4 +/- 2.1 mmol l-1) and daytime (11.5 +/- 2.4 vs 10.0 +/- 2.2 mmol l-1) plasma glucose concentrations (p less than 0.05). Fasting and postprandial plasma levels of C-peptide and insulin were unchanged. While fasting plasma lactate concentrations remained unaltered after metformin, a rise was noted in response to meals (from 1.4 +/- 0.1 to 1.8 +/- 0.2 mmol l-1, p less than 0.05). Adipocyte insulin receptor binding was unaffected by drug treatment. Moreover, no insulin-like effects or post-binding potentiation of insulin action could be found on adipocyte glucose transport, glucose oxidation, lipogenesis, glycolysis or antilipolysis. A complementary in vitro study using adipocytes from non-obese healthy volunteers failed to show any direct effect of metformin on adipocyte insulin binding or glucose transport and metabolism, at media drug concentrations corresponding to therapeutic plasma levels.
Adipose Tissue↗
Primordial birdheaded nanism associated with progressive ataxia, early onset insulin resistant diabetes, goiter and primary gonadal insufficiency. A new syndrome.
A new syndrome in two siblings with primordial birdheaded nanism, progressive ataxia, goiter, primary gonadal insufficiency and insulin resistant diabetes mellitus is presented. Plasma concentrations of TSH, PTH, LH, FSH, ACTH, glucagon and insulin all working through cell membrane receptors were elevated. A generalized cell membrane defect was suggested to be the pathophysiological abnormality in these patients.
Adolescent↗
Metformin improves peripheral but not hepatic insulin action in obese patients with type II diabetes.
UNLABELLED: Nine obese patients with Type II diabetes mellitus were examined in a double-blind cross-over study. Metformin 0.5 g trice daily or placebo were given for 4 weeks. At the end of each period fasting and day-time postprandial values of plasma glucose, insulin, C-peptide and lactate were determined, and in vivo insulin action was assessed using the euglycemic clamp in combination with [3-3H]glucose tracer technique. Metformin treatment significantly reduced mean day-time plasma glucose levels (10.2 +/- 1.2 vs 11.4 +/- 1.2 mmol/l, P less than 0.01) without enhancing mean day-time plasma insulin (43 +/- 4 vs 50 +/- 7 mU/l, NS) or C-peptide levels (1.26 +/- 0.12 vs 1.38 +/- 0.18 nmol/l, NS). Fasting plasma lactate was unchanged (1.57 +/- 0.16 vs 1.44 +/- 0.11 mmol/l, NS), whereas mean day-time plasma lactate concentrations were slightly increased (1.78 +/- 0.11 vs 1.38 +/- 0.11 mmol/l, P less than 0.01). The clamp study revealed that metformin treatment was associated with an enhanced insulin-mediated glucose utilization (370 +/- 38 vs 313 +/- 33 mg.m-2.min-1, P less than 0.01), whereas insulin-mediated suppression of hepatic glucose production was unchanged. Also basal glucose clearance was improved (61.0 +/- 5.8 vs 50.6 +/- 2.8 ml.m-2.min-1, P less than 0.05), whereas basal hepatic glucose production was unchanged (81 +/- 6 vs 77 +/- 4 mg.m-2.min-1, NS). CONCLUSIONS: 1) Metformin treatment in obese Type II diabetic patients reduces hyperglycemia without changing the insulin secretion.(ABSTRACT TRUNCATED AT 250 WORDS)
Blood Glucose↗