Carbohydrate and Lipid Metabolism in Relation to Body Composition in Myotonic Dystrophy

Björntorp, Per; Schröder, G.; Örndahl, G

doi:10.2337/diab.22.4.238

Cited by 16 publications

(6 citation statements)

References 11 publications

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“…Regardless of the mechanism of the pancreatic pathology in the R6/2 mouse or human HD, our results demonstrate that expanded polyglutamine repeats can produce diabetes. Other triplet repeat disorders such as Friedreich's ataxia (GAA repeat) and myotonic dystrophy (CTG repeat) have an increased incidence of diabetes, suggesting that there may be a common mechanism causing reduced pancreatic insulin production (15,16). The R6/2 transgenic mouse should prove to be a useful model for elucidating the mechanism of diabetes in Huntington's and other triplet repeat diseases.…”

Section: Discussionmentioning

confidence: 97%

Mice transgenic for an expanded CAG repeat in the Huntington's disease gene develop diabetes.

Hurlbert

Zhou²,

Wasmeier³

et al. 1999

Diabetes

199

122

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The autosomal dominant neurological syndrome of Huntington's disease has been modeled in transgenic mice by the expression of a portion of the human huntingtin gene together with 140 CAG repeats (the R6/2 strain). The mice develop progressive chorea with onset at approximately 9 weeks of age and with death at approximately 13 weeks. Associated symptoms include weight loss and polyuria in the absence of eating or drinking deficits. We have found that these mice have insulin-responsive diabetes. Fasting glucose was 211 + 19 mg/dl in R6/2 mice compared with 93 + 5 mg/dl in C57/B6 controls (n = 12, both groups; P < 0.01). Administration of insulin intraperitoneally led to a reduction in blood glucose. At 12.5 weeks, animals were killed and pancreas weighed and analyzed for insulin and glucagon. Pancreatic mass in R6/2 mice was the same as controls, and islets appeared normal in morphology without lymphocytic infiltration. Immunohistochemical staining showed dramatic reductions in glucagon in the alpha-cells and in insulin in the beta-cells. Direct tissue assays showed glucagon and insulin content were reduced to only 10 and 15% of controls, respectively. Diabetes has been reported as being more common in Huntington's disease and other triplet repeat disorders. The R6/2 mouse should prove useful for elucidating the mechanism of diabetes in these genetic diseases.

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Section: Discussionmentioning

confidence: 97%

Mice transgenic for an expanded CAG repeat in the Huntington's disease gene develop diabetes.

Hurlbert

Zhou²,

Wasmeier³

et al. 1999

Diabetes

199

122

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“…Recent investigations suggest that the hyperinsulinemia reflects generalized insulin resistance, and abnormal insulin tolerance test results support this conclusion (3,11). However, other researchers have observed normal insulin tolerance responses (6,9,12,13), and many myotonic dystrophy patients differ distinctly from other diseased patients with hyperinsulinemia, in that their basal insulin levels are normal (4,9,14,15,16). No abnormalities of endogenous insulin (6,8,10,16) or proinsulin (16) have been reported and a preliminary search for anti-insulin receptor antibody in one patient was unsuccessful (17).…”

Section: Introductionmentioning

confidence: 99%

Decreased insulin sensitivity of forearm muscle in myotonic dystrophy.

Moxley¹,

Griggs²,

Goldblatt³

et al. 1978

J. Clin. Invest.

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Previous studies of patients with myotonic dystrophy have demonstrated hyperinsulinism after glucose loading. This hyperinsulinism has been attributed by some investigators to tissue insulin resistance. We have directly studied insulin sensitivity of forearm muscle in patients having such hyperinsulinism. The effect of an intrabrachial arterial insulin infusion (100 mu U/kg per min) on glucose uptake was determined in six cases of myotonic dystrophy, six normal subjects, and in seven disease control subjects with myotonia or wasting from other disorders. There was no significant difference in insulin tolerance comparing myotonic dystrophy patients to the normal and disease control groups. Glucose tolerance and basal insulin levels were normal in the myotonic dystrophy patients, but hyperinsulinism occurred after glucose ingestion. After 25 min of intra-arterial insulin, the mean peak muscle glucose uptake in myotonic dystrophy was 2.54 +/- 0.54 mu mol/min per 100 ml forearm compared to 5.24 +/- 0.86 mu mol/min per 100 ml for disease controls (P is less than 0.05). Myotonic dystrophy patients showed a peak glucose uptake increment of only 2.6 +/- 0.2-fold over basal contrasted with the disease control value of 6.5 +/- 1.0-fold (P is less than 0.02) and the normal control value of 8.8 +/- 1.1-fold (P is less than 0.01). Thus, there was an absolute as well as a relative decrease in muscle insulin sensitivity in myotonic dystrophy patients compared to both control groups. The peak increments in arterio-superficial venous glucose concentration differences after insulin infusion were not significantly different comparing myotonic dystrophy and control groups. These data suggest that in myotonic dystrophy, there is insulin insensitivity of skeletal muscle.

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“…Mean k standard error coefficients of variation for the control subjects during the 20,80, and 200 mU/m2/rnin infusions were 5.1 t 0.7,6.1 t 0.4, and 5.8 +-0 . 3 …”

Section: Experimental Protocolmentioning

confidence: 99%

Whole body insulin resistance in myotonic dystrophy

Moxley

Corbett

Minaker

et al. 1984

Annals of Neurology

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To quantitate the degree of whole body insulin resistance in patients with myotonic dystrophy, three separate euglycemic insulin infusions were given to ambulatory patients and the results compared with findings in normal control subjects. Basal glucose and insulin values were similar for the two groups. There was no significant difference in insulin clearance rates between normal subjects and patients at the three insulin infusion rates used. A highly significant decrease in the whole body glucose disposal rate was seen during the 120-minute insulin infusion in the patients with myotonic dystrophy compared with normal subjects at all three insulin dosages (20 mU/m2/min: 2.18 +/- 0.29 [standard error] versus 5.49 +/- 1.72 mg/kg/min, p less than 0.0001; 80 mU/m2/min: 4.16 +/- 0.34 versus 8.49 +/- 0.45 mg/kg/min, p less than 0.0001; 200 mU/m2/min: 5.22 +/- 0.53 versus 10.06 +/- 0.50 mg/kg/min, p less than 0.0001). These marked decreases in glucose disposal rates for the patients were adjusted in accordance with their 24-hour urinary creatinine excretion rate to correct for the difference in muscle mass between patients and controls. This adjusted glucose disposal rate was 15 to 25% lower (p less than 0.02) in the patients with myotonic dystrophy at insulin infusion rates of 20 and 80 mU. During the 200 mU insulin infusions, the adjusted glucose disposal rate remained lower than that in normal subjects but was of borderline statistical significance. These studies suggest that moderately severe whole body insulin resistance is responsible for the postprandial hyperinsulinemia typically seen in patients with myotonic dystrophy.

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Carbohydrate and Lipid Metabolism in Relation to Body Composition in Myotonic Dystrophy

Cited by 16 publications

References 11 publications

Mice transgenic for an expanded CAG repeat in the Huntington's disease gene develop diabetes.

Mice transgenic for an expanded CAG repeat in the Huntington's disease gene develop diabetes.

Decreased insulin sensitivity of forearm muscle in myotonic dystrophy.

Whole body insulin resistance in myotonic dystrophy

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