Steven M. Willi

Benefits of continuous subcutaneous insulin infusion in children with type 1 diabetes

OBJECTIVE To examine the effect of continuous subcutaneous insulin infusion (CSII) therapy on parameters affecting long-term outcome in type 1 diabetes. Study design Height, weight, body mass index, insulin dose, glycosylated hemoglobin (HbA(1C)), and blood glucose data from home meter downloads were collected prospectively for analysis in 51 children (age, 10.7+/-3.1 years, mean+/-SD) throughout the 12 months before and after introducing CSII. RESULTS Before pump initiation, HbA(1C) was relatively stable, but it fell to 7.7+/-0.2% (P<.001) within 3 months of CSII and remained decreased (7.9+/-0.1%) at 12 months (P<.01). In contrast, weight standard deviation score increased before CSII (from 0.50+/-0.13 to 0.60+/-0.13, P<.05), but remained unchanged (0.61+/-0.11) in the year thereafter. Although severe hypoglycemia (<50 mg/dL) was reduced in the entire cohort, HbA(1C) improved primarily in young children and teenagers. Comparison of glycemic responders (HbA(1C) <7.5, or a decrease >1% on CSII, n=23) with nonresponders demonstrated no differences with respect to gender, socioeconomic status, weight standard deviation score, body mass index, initial HbA(1C), frequency of hypoglycemia, or number of education visits before CSII. CONCLUSION Continuous subcutaneous insulin infusion is effective in lowering HbA(1C) and the occurrence of severe nocturnal hypoglycemia without excessive weight gain in most children with type 1 diabetes. HbA(1C) response to CSII is poorer in preadolescents than in young children or teenagers.

Genealogy, natural history, and phenotype of Alstrom syndrome in a large Acadian kindred and three additional families.

We describe a large Acadian kindred including 8 Alstrom Syndrome (AS) patients, with an age range of 4 to 26 at the time of clinical assessment. The affected subjects come from 5 nuclear families within this kindred. The phenotype includes early childhood retinopathy, progressive sensorineural hearing loss, truncal obesity, and acanthosis nigricans. In addition, hyperinsulinemia and hypertriglyceridemia with normal cholesterol levels were observed in most affected individuals tested. Non-insulin dependent diabetes mellitus and growth retardation appear to be age-related manifestations that occur post-adolescence. Younger affected children are not overtly hyperglycemic and are normal or above average height for age. Although the AS patients in kindred 1 presumably carry the same mutation, many manifestations of the disease are variable. For example, of the 8 children in the Acadian kindred, 4 have scoliosis, 2 have had infantile cardiomyopathy, 2 are hypothyroid, 1 has had hepatic dysfunction and is hypertensive, and 4 have developed asthma. Seven subjects described in this kindred exhibit developmental delay. One additional manifestation not described widely in the literature, advanced bone age, was observed in all subjects tested. The clinical data from this large Acadian kindred, together with information obtained from 4 additional AS patients in 3 unrelated kindreds, confirm and extend clinical observations previously described. In addition, the Acadian kindred with multiple affected individuals, probably arising from a common founder, should allow for identification of the chromosomal localization of a gene causing AS.

Effective use of thiazolidinediones for the treatment of glucocorticoid-induced diabetes.

We evaluated the efficacy of a thiazolidinedione in the treatment of diabetes induced by glucocorticoids. We examined the effectiveness of troglitazone in seven patients with long-standing steroid-induced diabetes. Five of the seven subjects were treated with insulin alone, one was treated with both insulin and oral therapy and one was treated with oral therapy alone. The mean insulin dose in six of the seven subjects was 0.66+/-0.09 units/kg per day. Diabetes status was assessed by measuring serum fructosamine, HgbA1c, oral glucose and meal tolerance tests (OGTT and MTT) at baseline and after treatment for 5-8 weeks with troglitazone 400 mg/day. Troglitazone caused a significant decrease in fructosamine (274+/-32 vs. 217+/-22 mmol/l; P<0.01) and HgbA1C (7.8+/-0.4 vs. 7.2+/-0.4%; P<0.01) as well as decrements in the areas under the OGTT 2,308+/-156 vs. 1,937+/-127 mmol/l; P<0.05) and MTT glucose curves (4694+/-449 vs. 4057+/-437 mmol/l; P<0.05). In addition, the area under the insulin curve for the oral glucose tolerance test showed a significant increase from 27,438+/-4,488 to 41,946+/-6,048 pmol/l (P<0.05). Total and LDL cholesterol were also significantly decreased (6.4+/-0.9 vs. 5.0+/-0.6 mmol/l and 3.8+/-0.7 vs. 2.7+/-0.4 mmol/l, respectively, P<0.05). Fasting leptin values decreased by 23% despite an increase in body weight. Troglitazone is effective in the treatment of glucocorticoid-induced diabetes as manifested by lower measures of glycemia, HgbA1c, and post-prandial glucose values, while the doses of other diabetes medications remained unchanged or were reduced. The insulin-sensitizing drug also produced a marked increase in endogenous insulin secretion in response to glucose, lower total and LDL cholesterol, and decreased fasting leptin despite weight gain. Thiazolidinediones may improve diabetes-related parameters by antagonizing pathways of glucocorticoid-induced insulin resistance and by reversing adverse effects of glucocorticoids on beta cell function.

Endogenous mutations in human uncoupling protein 3 alter its functional properties

Human uncoupling protein 3 (UCP3) is a mitochondrial transmembrane carrier that uncouples oxidative phosphorylation and is a candidate gene for obesity. Expression of native human UCP3 mutations in yeast showed complete loss (R70W), significant reduction (R143X), or no effect (V102I and IVS6+1G>A) on the uncoupling activity of UCP3. It is concluded that certain mutations in UCP3 alter its functional impact on membrane potential (ΔΨ), possibly conferring susceptibility to develop metabolic diseases.

Type 2 diabetes mellitus in adolescents

Type 2 diabetes has traditionally been considered an adult disease, with increasing incidence in older age groups. However, a number of clinical and epidemiologic reports have suggested an increasing occurrence of type 2 diabetes over time among children and adolescents. Among Native Americans, the prevalence is approaching 5% in some age groups, and other minority populations are not far behind. Although the majority of children appear to have a form of diabetes that is very similar to type 2 diabetes in adults, at least two subtypes, maturity onset diabetes of the young (MODY) and “atypical diabetes,” also appear to be occurring with increased frequency. A number of attributes may indicate a predisposition to type 2 diabetes in minority youths. Significant risk factors include ethnicity, family history, obesity, low (or high) birth weight, acanthosis nigricans, and a sedentary lifestyle. To date, there is no uniform agreement on the diagnostic criteria for type 2 diabetes in adolescents. However, the combination of obesity, a positive family history of type 2 diabetes, and the absence of antibodies to islet cell antigens is highly suggestive of type 2 diabetes. Genetic testing, which is already possible for many of the MODYs, may soon allow for the identification of individuals at very high risk. As the number of treatment options for type 2 diabetes expands, it remains important to temper enthusiasm for new agents with considerable caution, in light of the possibility that unanticipated side-effects may be more common in children.

Decreased hexosamine biosynthesis in GH-deficient dwarf rat muscle. Reversal with GH, but not IGF-I, therapy

Enhanced glucose flux via the hexosamine biosynthesis pathway (HNSP) has been implicated in insulin resistance. We measuredl-glutamine:d-fructose-6-phosphate amidotransferase activity (GFAT, a rate-limiting enzyme) and concentrations of UDP- N-acetyl hexosamines (UDP-HexNAc, major products of HNSP) in muscle and liver of growth hormone (GH)-deficient male dwarf (dw) rats. All parameters measured, except body weight, were similar in 5-wk-old control and dw rats. Muscle GFAT activity declined progressively with age in controls and dw rats but was consistently 30-60% lower in 8- to 14-wk-old dw rats vs. age-matched controls; UDP-HexNAc concentrations in muscle were concomitantly 30% lower in dw rats vs. controls ( P < 0.01). Concentrations of UDP-hexoses, GDP-mannose, and UDP in muscle were similar in control and dw rats. Muscle HNSP activity was similarly diminished in fed and fasted dw rats. In liver, only a small difference in GFAT activity was evident between controls and dw rats, and no differences in UDP-HexNAc concentrations were observed. Treatment with recombinant human GH (rhGH) for 5 days restored UDP-HexNAc to control levels in dw muscles ( P < 0.01) and partially restored GFAT activity. Insulin-like growth factor I treatment was ineffective. We conclude that GH participates in HNSP regulation in muscle.Enhanced glucose flux via the hexosamine biosynthesis pathway (HNSP) has been implicated in insulin resistance. We measured L-glutamine:D-fructose-6-phosphate amidotransferase activity (GFAT, a rate-limiting enzyme) and concentrations of UDP-N-acetyl hexosamines (UDP-HexNAc, major products of HNSP) in muscle and liver of growth hormone (GH)-deficient male dwarf (dw) rats. All parameters measured, except body weight, were similar in 5-wk-old control and dw rats. Muscle GFAT activity declined progressively with age in controls and dw rats but was consistently 30-60% lower in 8- to 14-wk-old dw rats vs. age-matched controls; UDP-HexNAc concentrations in muscle were concomitantly 30% lower in dw rats vs. controls (P < 0.01). Concentrations of UDP-hexoses, GDP-mannose, and UDP in muscle were similar in control and dw rats. Muscle HNSP activity was similarly diminished in fed and fasted dw rats. In liver, only a small difference in GFAT activity was evident between controls and dw rats, and no differences in UDP-HexNAc concentrations were observed. Treatment with recombinant human GH (rhGH) for 5 days restored UDP-HexNAc to control levels in dw muscles (P < 0.01) and partially restored GFAT activity. Insulin-like growth factor I treatment was ineffective. We conclude that GH participates in HNSP regulation in muscle.

Atypical diabetes mellitus: time for a consensus?

Abstract: A subgroup of diabetic patients presents with features typical of type 1 diabetes, but over months to years has variable insulin requirements and develops features of type 2 diabetes. This subgroup is referred to as atypical diabetes mellitus (ADM). Over a span of 50 yr, reports on disease epidemiology, clinical characteristics, and metabolic/genetic features of the entity now referred to as ADM remain conflicted. This article reviews the available literature on ADM, proposes atypical diabetes mellitus syndrome (ADMS) as an encompassing nomenclature, and recommends expansive criteria for disease definition pending the release of a consensus recommendation by a panel of experts.