F. Arnold Gries

Assessment of small and large fiber function in long-term type 1 (insulin-dependent) diabetic patients with and without painful neuropathy.

&NA; Twelve neural function tests (thermal discrimination thresholds, pain perception thresholds to heat and cold stimuli, vibration perception thresholds, and motor and sensory nerve conduction velocities) were assessed in the lower and upper extremities of 60 long‐term type 1 diabetic patients. Thirty patients were asymptomatic (group 1) and 30 patients had painful neuropathy (group 2), predominantly originating in the distal lower limbs (group 2a; n = 20) or in the distal upper limbs (group 2b; n = 10). There were no significant differences between the groups with regard to age, duration of diabetes or glycemic control. Eleven of the 12 functions tested (6 in lower and upper limbs, respectively) were significantly diminished in both groups of diabetics as compared to age‐matched control subjects. Group 2a had significant impairment in 5 of 6 parameters of the lower limbs, while in group 2b only 1 of 6 functions of the upper limbs was diminished. In the whole diabetic group, the most frequent abnormality was an elevated threshold for thermal sensation in the foot. Significant correlations between small and large fiber abnormalities were observed predominantly in the foot. Selective affection of small or large fiber functions showed different patterns in the arms and in the legs. In the upper extremities selective impairment in nerve conduction was predominant, while in the lower extremities it was thermal sensation. These findings suggest that both generalized and selective small or large fiber affection may occur in long‐term type 1 diabetic patients. Dysfunction of both modalities is more severe in the lower limbs, when painful symptoms have developed in this region.

Blood amino acid levels in patients with insulin excess (functioning insulinoma) and insulin deficiency (diabetic ketosis)

Blood amino acid concentrations were determined in the postabsorptive state in nine patients with insulin excess (functioning insulinomas), nine juvenile-type diabetics with insulin deficiency (diabetic ketosis due to insulin withdrawal), six juvenile diabetics in moderate metabolic control, and five healthy control subjects. Blood branched-chain amino acid (BCAA) levels were elevated in diabetic ketosis and decreased in patients with insulinomas. Blood concentrations of BCAA were significantly correlated to blood glucose levels, and in diabetics they were also correlated to blood ketone bodies, serum free fatty acids, and glycerol levels. These data indicate an inverse relationship between circulating effective insulin levels and blood BCAA concentrations. It is suggested that blood levels of BCAA might represent an indicator of insulin-dependent alterations of protein metabolism.

One-year treatment with the aldose reductase inhibitor, ponalrestat, in diabetic neuropathy

A double blind placebo controlled trial was performed to evaluate the effects of the aldose reductase inhibitor, ponalrestat, on symptomatic diabetic neuropathy. After a 4-week placebo run-in phase, 60 patients were 2:1 randomized to receive either 600 mg ponalrestat or placebo once daily over 12 months. Forty-six patients, 30 of whom were treated with ponalrestat and 16 with placebo, completed the study. Motor and sensory nerve conduction, thermal and vibration sensation thresholds, heart rate variation at rest, E/I ratio, pupillary dilation velocity and pupillary reflex latency were determined at baseline and after 6 and 12 months. Neuropathic symptom scores were assessed every 3 months. Among the fifteen nerve function parameters studied, only trends in favour of ponalrestat were noted for heart rate variation and E/I ratio after 6 months (P = 0.06), but no significant differences between the groups could be demonstrated during the study. No adverse reactions were observed. It is concluded that one-year treatment with ponalrestat has no beneficial effects on symptoms or electrophysiological parameters in diabetic neuropathy.

Linear Loss of Insulin Secretory Capacity During the Last Six Months Preceding IDDM: No effect of antiedematous therapy with ketotifen

OBJECTIVE To investigate the effect of an antiedematous therapy with the histamine antagonist ketotifen on β-cell function in late prediabetes. RESEARCH DESIGN AND METHODS In a randomized double-blind placebo-controlled study, ketotifen was administered for 3 months to 9 islet cell antibody positive (ICA+) prediabetic patients with a first-phase insulin response (FPIR) below the 2.5th percentile to preserve residual β-cell function. Patients were followed by intravenous glucose tolerance tests (IVGTTs) every 4—6 weeks for determination of FPIR, HbA1, ICAs, and insulin autoantibodies. In 5 patients, the immune activation state was followed by determination of serum levels of tumor necrosis factor-α (TNF-α), (β2-microglobulin, and C-reactive protein (CRP). RESULTS Seven of nine patients developed diabetes within one year of followup. Irrespective of treatment with ketotifen, a slow and linear decline (P < 0.05) of 1 + 3-min insulin values was observed in sequential IVGTTs in those 7 patients who developed insulin-dependent diabetes mellitus (IDDM) during follow-up. The 2 other patients showed wide fluctuations of the insulin response with a threefold increase of initial insulin levels. HbAi did not correlate with FPIR. Fasting blood glucose increased significantly during the study (P < 0.05). Individual levels of serum TNF-α, CRP, and β2-microglobulin did not change during the study. CONCLUSIONS The study could not demonstrate preservation of β-cell function by ketotifen in the late stage before manifestation of clinical diabetes. Manifestation is preceded in the last 6 months by a steady loss of the FPIR without rapid deterioration immediately before diagnosis and without signs of increased immune activity.

Alternative therapeutic principles in the prevention of microvascular and neuropathic complications

Since the prevention of chronic diabetic complications by near normal metabolic control is not always achievable, alternative therapeutic principles have been developed. The specific intervention at metabolic abnormalities which seem to play a key role in the pathogenesis of complications has been shown to prevent the development of microangiopathy and neuropathy in experimental diabetes, e.g. inhibition of non-enzymatic glycation by aminoguanidine, inhibition of polyol pathway activity by aldose reductase inhibitors, prevention of hypoxia and oxidative stress by vasodilators and radical scavengers such as alpha-lipoic acid. Some of these drugs should soon be available for common clinical use.

Regulation of diabetic serum growth factors for human vascular cells by the metabolic control of diabetes mellitus

Serum factors from non-ketotic poorly controlled non-insulin-dependent diabetic patients stimulated growth and protein synthesis of human arterial smooth muscle cells and fibroblasts by 15-42%, compared to serum factors from well controlled diabetics. In contrast, the growth stimulating effect of pooled sera from well controlled diabetics did not differ from the effect of normal sera. Single sera from the same diabetics before and after improvement of the metabolic control stimulated cell growth to a similar degree as the respective pooled sera from different diabetic populations. As far as increased growth stimulation of vascular cells is related to increased angiopathic risk in diabetics, this metabolic regulation of growth factors supports the demand for a continuous optimal control of diabetic metabolism.

Therapie der Adipositas

Das Ziel der Therapie der Adipositas ist die Pravention bzw. Linderung der mit der Fettsucht einhergehenden Begleit- und Folgekrankheiten, der Stoffwechselanomalitaten, somatischen und psychischen Storungen. Die Lebenserwartung ist bei Adipositas eingeschrankt (vergl. Epidemiologie der Fettsucht). Der direkte zahlenmasige Nachweis einer Besserung der Lebenserwartung durch Gewichtsabnahme ist bislang erst in einer Studie an Lebensversicherungsklienten untersucht und belegt worden (Abb. 1). Die Ruckbildung der mit der Fettsucht assoziierten kardiovaskularen Risikofaktoren durch Senkung des Ubergewichtes ist aber vielfach nachgewiesen worden (vergl. Pathophysiologie und Klinik). Die uberwiegende Zahl aller Adiposen weist einen oder mehrere kardiovaskulare Risikofaktoren auf. Diese fehlen nur bei jungeren Patienten und bei kurzdauernder Adipositas, mit ihrem spateren Auftreten ist in aller Regel zu rechnen (Berchtold et al., 1975).

Proinsulin autoantibodies: association with type I diabetes but not with islet cell antibodies, insulin autoantibodies or HLA-DR type.

Antibodies reacting with proinsulin but not with insulin determinants have been observed recently in Type I diabetes. We describe here that ELISA-determined proinsulin autoantibodies (IgG-PAA) also occur in first-degree relatives of IDDM patients (38/513, 7.4% vs 1.9% in controls, P less than 0.025). In contrast to insulin autoantibodies (IgG-IAA) and islet cell antibodies (ICA) no association with HLA type was found. Furthermore, IgG-PAA occur independently of IgG-IAA and ICA. We conclude that the humoral autoimmune response to proinsulin determinants is under separate genetic control.

Pathophysiologie der Adipositas

Der menschliche Organismus kann seinen Energiegehalt nur vermehren, wenn die Kalorienzufuhr den Bedarf ubersteigt. Deckt die Zufuhr den Bedarf nicht, tritt unvermeidlich ein Substanzverlust ein. Die Vermehrung der Fettdepots, sofern diese nicht auf Kosten anderer Gewebe erfolgt, hat also eine Uberernahrung zur Voraussetzung.

A comparison of the lipolytic effects of β1–24-corticotropin and extracted porcine ACTH

Abstract The lipolytic effects of highly purified native porcine ACTH and synthetic β 1–24 -corticotropin were compared on basis of their corticotropic potency. Both hormone preparations induced release of FFA from rat adipose tissue when added in vitro. The dose response curves were similar. The minimal effective concentration of the native ACTH was 2.4 × 10 −7 IU/ml.; that of the synthetic preparation was 2.3 × 10 −7 IU/ml. During prolonged incubation of both preparations hormone dependent lipolysis decreased to a similar degree, probably due to a similar instability of both peptides in the in vitro system. Both preparations caused a significant elevation of plasma FFA levels when injected into human subjects. Again, there was no difference in potency between the two preparations.