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The past 200 years have brought an understanding of diabetes and its pathogenesis, as well as the development of treatments that could not have been predicted when the disorder was first clinically described 2000 years ago. Beginning in the late 19th century, the initial descriptions of the microscopic anatomy of the pancreatic islets by Langerhans led to recognition of pancreatic endocrine function. Many investigators attempted to isolate the hypoglycemic factor produced by the pancreas, but Banting, Best, Macleod, and Collip were able to extract and purify “isletin” to treat human diabetes in 1921. Rapid scientific progress over the next 100 years led to an understanding of insulin synthesis, structure and function, production of modified synthetic insulins, and the physiopathology that permitted classification of diabetes subtypes. Improvements in control of diabetes have reduced the risks of complications. In less than two hundred years, we have gone from being unable to measure glucose in blood to being able to offer people with diabetes continuous blood glucose monitoring, linked to continuous subcutaneous insulin infusion. We come ever closer with new drugs and treatments to repair the biochemical defects in type 2 diabetes and to biologically replace islets and their function in type 1 diabetes. This review addresses the history of continuing progress in diabetes care.

Background: Liver function test (LFT) abnormalities, which may reflect underlying pathophysiology, are a well-known feature of Turner syndrome. Less frequently, liver findings may include vascular changes and, rarely, severe liver disease. Although previous studies on children and adolescents suggest a frequency of LFT abnormalities of up to 60%, less is known about the age at onset and natural history. Methods: We report a now 19-year-old young woman with Turner syndrome mosaicism with elevated transaminase levels first detected at the age of 2 years. We also present a retrospective analysis of 179 girls and women followed in the MassGeneral Hospital Turner Syndrome Clinic. Results: In the index case, the severity of liver function test abnormalities fluctuated without complete resolution from 2 to 18 years of age. In the full cohort of 179 patients, when lab results were available, elevated ALT levels occurred in 16 (11%) subjects of all ages, and in 5 (10%) patients ≤18 years of age. Significant and persistent ALT elevations occurred in 2 patients Conclusion: The updated Clinical Practice Guidelines for the care of girls and women with Turner syndrome recommend annual liver function tests throughout the lifespan, starting at the age of 10 years. Based on our data showing persistent elevation of at least one liver enzyme, we recommend a prospective and more comprehensive study of liver function in younger patients with Turner syndrome. An improved estimate of prevalence could better inform age-adjusted guidelines.

Gluconeogenesis from lactate may be qualitatively identified in the chronically catheterized baboon fetus in the maternal fed and fasted state. Infusion of 250 μCi U-14C-lactate to the fetus over a 150-min period leads to the appearance of 14C-glucose in the fetal circulation. Little 14C-lactate or glucose appears in the maternal circulation, supporting fetal production of glucose from lactate. Maternal glucose infusion seems to inhibit fetal gluconeogenesis. The mean plateau in percent disintegrations per minute of glucose compared to lactate in the maternal fed state is 14.7 ± 2.2 compared to 16.1 ± 3.0 in the maternal fasting state and 11.1 ± 0.6 during maternal glucose infusion. It is clear that the primate fetus is capable of gluconeogenesis before term. Quantitation of this capacity awaits development of a model permitting assessment of maternal-placental and fetal substrate flux.

In 6 growth hormone-deficient children, we have demonstrated that 3-N-demethylation of caffeine as measured by the 13CO2 caffeine breath test is decreased following 1 month of growth hormone therapy (8.4 +/- 1.0 vs. 6.8 +/- 1.2% 13C/2 h after treatment). These findings could be of clinical importance. The initiation of growth hormone therapy in growth hormone-deficient children could alter the clearance of drugs metabolized through the mixed-function oxidase pathway given for concurrent conditions, and necessitate adjustment of the therapeutic regimen.

Experimental intrauterine growth retardation was produced in two groups of neonatal rats by maternal sham surgery or by maternal obligatory exercise during the last 5 days of gestation (forced swim). Both experimental groups of neonates had lower plasma glucose and higher plasma insulin levels than controls after a 4-hour fast. Fetal stunting may be produced by a variety of maternal stresses in the rat and may be associated with alterations in the hormonal and glycemic response to fasting. Studies of the metabolic effects of experimental intrauterine growth retardation must be interpreted with caution if control animals have been subjected to intrauterine stress.

Renal and hepatic levels of the rate-limiting gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK) were determined in control and intrauterine growth-retarded rate neonates and dams. Dexamethasone and surgically induced intrauterine growth retardation (IUGR) resulted in an elevation of neonatal renal PEPCK activity, but did not affect hepatic PEPCK levels. In the dam, glucocorticoid administration resulted in an increase in renal PEPCK, but did not affect the hepatic enzyme. We have demonstrated that, unlike the hepatic enzyme, renal PEPCK could potentially contribute to gluconeogenesis in utero, since dexamethasone administration significantly increased renal PEPCK at birth. This study confirms the hypothesis that hepatic and renal PEPCK activities are regulated independently in both the adult and neonatal animal.

Experimental intrauterine growth retardation was produced in two groups of neonatal rats by maternal dietary restriction (DR) or by bilateral ligation of the uterine vessels (UVL). Both experimental groups of neonates had lower plasma glucose levels than controls at delivery. Newborns of DR animals showed appropriate suppression of insulin release and rapid recovery from hypoglycemia during an 8-hour fast. In contrast, neonates in the UVL group displayed persistently lower plasma glucose levels and inappropriate hyperinsulinemia. The metabolic effects of these two models of intrauterine growth retardation reflect the nature of the fetal insult and are not uniform.