This review considers the epidemiologic evidence of an increasing incidence of type 2 diabetes in youth, the classification and diagnostic issues related to diabetes in young populations, pathophysiologic mechanisms relevant to the increasing incidence, the role of genetics and environment, and the community challenge for prevention and treatment. Type 2 diabetes in youth has been recognized to be frequent in populations of native North Americans and to comprise some 30 percent of new cases of diabetes in the 2nd decade of life, largely accounted for by minority populations and associated with obesity. Among Japanese schoolchildren, type 2 diabetes is seven times more common than type 1, and its incidence has increased more than 30-fold over the past 20 years, concomitant with changing food patterns and increasing obesity rates. The forms of diabetes seen in children and youth include typical type 1, occurring in all races; type 2, seen predominantly in minority youth; atypical diabetes, seen as an autosomal dominantly transmitted disorder in African-American populations; and maturity-onset diabetes of the young (MODY), seen rarely and only in Caucasians. Of the nonautoimmune forms of diabetes seen in youth, only type 2 diabetes is increasing in incidence. Proper classification requires consideration of onset (acute/severe versus insidious), ethnicity, family history, presence of obesity, and if necessary, studies of diabetes related autoimmunity. Insulin resistance predicts the development of diabetes in Pima Indians, in offspring of parents with type 2 diabetes, and in other high-risk populations. African-American children and youth have greater insulin responses during glucose tolerance testing and during hyperglycemic clamp study than do whites. There is also evidence of altered beta-cell function preceding the development of hyperglycemia. Of particular interest is the evidence that abnormal fetal and infantile nutrition is associated with the development of type 2 diabetes in adulthood. The thrifty phenotype hypothesis states that poor nutrition in fetal and infant life is detrimental to the development and function of the beta-cells and insulin sensitive tissues, leading to insulin resistance under the stress of obesity. The thrifty genotype hypothesis proposes that defective insulin action in utero results in decreased fetal growth as a conservation mechanism, but at the cost of obesity-induced diabetes in later childhood or adulthood. The vast majority of type 2 diabetes in adults is polygenic and associated with obesity. Monogenic forms (MODY, maternally transmitted mitochondrial mutations) are rare, but are more likely to appear in childhood. Linkage studies of the common polygenic type 2 diabetes have emphasized the heterogeneity of the disorder. The prevention and treatment of type 2 diabetes in children and youth is a daunting challenge because of the enormous behavioral influence, difficulty in reversing obesity, and typical nonadherence in this age-group. The emerging epidemic of type 2 diabetes i...

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Sixty-nine instances of intracerebral complications of diabetic ketoacidosis (DKA), including 29 unpublished occurrences, were analyzed to determine predictive factors, the frequency of other disorders resembling cerebral edema, the effectiveness of intervention to reduce intracranial pressure, and whether any etiologic considerations appeared valid. The review failed to implicate rate of hydration, tonicity of administered fluids, rate of correction of glycemia, or use of bicarbonate. Infants and young children (less than 5 yr of age) were disproportionately represented (33%), as were new-onset patients (62%). Approximately 20% of patients were found to have localized basilar edema, hemorrhage, thromboses, or infection by computed tomography scan or on postmortem examination. The histories of 50% of the patients suggested a period of dramatic neurological change preceding respiratory arrest (RA) during which intervention might be effective. Twenty-three patients were treated for increased intracranial pressure before RA; 13 patients survived in an independent functional state, and 3 survived in a severely disabled or vegetative state. Only 3 of the remaining 46 patients survived normally: 2 were untreated and never developed RA, and 1 was given mannitol at the onset of apnea. This review supports close neurological monitoring and intervention to reduce intracranial pressure when there are definite signs of neurological compromise. However, treatment appears to be successful in only 50% of patients who give sufficient warning for such intervention, and they comprised half of the study population. Therefore, prevention of DKA remains the most important goal to avoid intracerebral complications.

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We detected limited mobility of small and large joints in 92 (30 per cent) of 309 patients with diabetes who were one to 28 years old. Among patients who had had diabetes for more than 4.5 years (the shortest duration at which microvascular complications were noted), 82 of 169 had joint limitation. Forty-one of these 82 also had microvascular complications, but only 10 of the 87 patients without joint limitation had complications. Life-table analysis indicated an 83 per cent risk for microvascular complications after 16 years of diabetes if joint limitation was present, but only a 25 per cent risk if joint limitation was absent. Consequently, limited joint mobility identifies a population exceptionally at risk for the early development of microvascular complications, and intervention to forestall or prevent these complications can now be focused.

Patients with pseudohypoparathyroidism type Ib (PHP-Ib) have hypocalcemia and hyperphosphatemia due to renal parathyroid hormone (PTH) resistance, but lack physical features of Albright hereditary osteodystrophy. PHP-Ib is thus distinct from PHP-Ia, which is caused by mutations in the GNAS exons encoding the G protein α subunit. However, an imprinted autosomal dominant form of PHP-Ib (AD-PHP-Ib) has been mapped to a region of chromosome 20q13.3 containing GNAS. Furthermore, loss of methylation at a differentially methylated region (DMR) of this locus, exon A/B, has been observed thus far in all investigated sporadic PHP-Ib cases and the affected members of multiple AD-PHP-Ib kindreds. We now report that affected members and obligate gene carriers of 12 unrelated AD-PHP-Ib kindreds and four apparently sporadic PHP-Ib patients, but not healthy controls, have a heterozygous approximately 3-kb microdeletion located approximately 220 kb centromeric of GNAS exon A/B. The deleted region, which is flanked by two direct repeats, includes three exons of STX16, the gene encoding syntaxin-16, for which no evidence of imprinting could be found. Affected individuals carrying the microdeletion show loss of exon A/B methylation but no epigenetic abnormalities at other GNAS DMRs. We therefore postulate that this microdeletion disrupts a putative cis-acting element required for methylation at exon A/B, and that this genetic defect underlies the renal PTH resistance in AD-PHP-Ib.

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