It’s a great honor to join the exceptional club of Banting Award winners, many of whom were my role models and mentors. In addition, giving the Banting Lecture also has a very personal meaning to me, because without Frederick Banting, I would have died from type 1 diabetes when I was 8 years old. However, it was already apparent at the time I was diagnosed that for too many people like me, Banting’s discovery of insulin only allowed them to live just long enough to develop blindness, renal failure, and coronary disease. For example, when I started college, the American Diabetes Association’s Diabetes Textbook had this to say to my parents: “The person with type 1 diabetes can be reassured that it is highly likely that he will live at least into his 30s.” Not surprisingly, my parents did not find this particularly reassuring.

At the same time we were reading this in 1967, however, the first basic research discovery about the pathobiology of diabetic complications had just been published in Science the previous year. In my Banting Lecture today, I am thus going to tell you a scientific story that is also profoundly personal.

I’ve divided my talk into three parts. The first part is called “pieces of the puzzle,” and in it I describe what was learned about the pathobiology of diabetic complications starting with that 1966 Science paper and continuing through the end of the 1990s. In the second part, I present a unified mechanism that links together all of the seemingly unconnected pieces of the puzzle. Finally, in the third part, I focus on three examples of novel therapeutic approaches for the prevention and treatment of diabetic complications, which are all based on the new paradigm of a unifying mechanism for the pathogenesis of diabetic complications. …

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The pathobiology of diabetic complications: a unifying mechanism.

In this book, Andrew Harvey sets out to provide a unified and comprehensive theory of structural time series models. Unlike the traditional ARIMA models, structural time series models consist explicitly of unobserved components, such as trends and seasonals, which have a direct interpretation. As a result the model selection methodology associated with structural models is much closer to econometric methodology. The link with econometrics is made even closer by the natural way in which the models can be extended to include explanatory variables and to cope with multivariate time series. From the technical point of view, state space models and the Kalman filter play a key role in the statistical treatment of structural time series models. The book includes a detailed treatment of the Kalman filter. This technique was originally developed in control engineering, but is becoming increasingly important in fields such as economics and operations research. This book is concerned primarily with modelling economic and social time series, and with addressing the special problems which the treatment of such series poses. The properties of the models and the methodological techniques used to select them are illustrated with various applications. These range from the modellling of trends and cycles in US macroeconomic time series to to an evaluation of the effects of seat belt legislation in the UK.

Forecasting, Structural Time Series Models and the Kalman Filter

Sarcopenia in Asia: consensus report of the Asian Working Group for Sarcopenia.

ContextComplications of atherosclerosis cause most morbidity and mortality
in patients with diabetes mellitus. Despite the frequency and severity of
disease, proven medical therapy remains incompletely understood and underused.ObjectiveTo review the epidemiology, pathophysiology, and medical and invasive
treatment of atherosclerosis in patients with diabetes mellitus.Data SourcesUsing the index terms diabetes mellitus, myocardial infarction, peripheral vascular
diseases, cerebrovascular accident, endothelium, vascular smooth muscle, platelets, thrombosis, cholesterol, hypertension, hyperglycemia, insulin, angioplasty, and coronary artery bypass, we
searched the MEDLINE and EMBASE databases from 1976 to 2001. Additional data
sources included bibliographies of identified articles and preliminary data
presented at recent cardiology conferences.Study SelectionWe selected original investigations and reviews of the epidemiology,
pathophysiology, and therapy of atherosclerosis in diabetes. We selected randomized,
double-blind, controlled studies, when available, to support therapeutic recommendations.
Criteria for data inclusion (168 of 396) included publication in a peer-reviewed
journal or presentation at a national cardiovascular society–sponsored
meeting.Data ExtractionData quality was determined by publication in peer-reviewed literature.
Data extraction was performed by one of the authors.Data SynthesisDiabetes mellitus markedly increases the risk of myocardial infarction,
stroke, amputation, and death. The metabolic abnormalities caused by diabetes
induce vascular dysfunction that predisposes this patient population to atherosclerosis.
Blood pressure control, lipid-lowering therapy, angiotensin-converting enzyme
inhibition, and antiplatelet drugs significantly reduce the risk of cardiovascular
events. Although diabetic patients undergo revascularization procedures because
of acute coronary syndromes or critical limb ischemia, the outcomes are less
favorable than in nondiabetic cohorts.ConclusionsSince most patients with diabetes die from complications of atherosclerosis,
they should receive intensive preventive interventions proven to reduce their
cardiovascular risk.

Diabetes and atherosclerosis: epidemiology, pathophysiology, and management.

ContextAmong persons diagnosed as having diabetes mellitus, the prevalence
of foot ulcers is 4% to 10%, the annual population-based incidence is 1.0%
to 4.1%, and the lifetime incidence may be as high as 25%. These ulcers frequently
become infected, cause great morbidity, engender considerable financial costs,
and are the usual first step to lower extremity amputation.ObjectiveTo systematically review the evidence on the efficacy of methods advocated
for preventing diabetic foot ulcers in the primary care setting.Data Sources, Study Selection, and Data ExtractionThe EBSCO, MEDLINE, and the National Guideline Clearinghouse databases
were searched for articles published between January 1980 and April 2004 using
database-specific keywords. Bibliographies of retrieved articles were also
searched, along with the Cochrane Library and relevant Web sites. We reviewed
the retrieved literature for pertinent information, paying particular attention
to prospective cohort studies and randomized clinical trials.Data SynthesisPrevention of diabetic foot ulcers begins with screening for loss of
protective sensation, which is best accomplished in the primary care setting
with a brief history and the Semmes-Weinstein monofilament. Specialist clinics
may quantify neuropathy with biothesiometry, measure plantar foot pressure,
and assess lower extremity vascular status with Doppler ultrasound and ankle-brachial
blood pressure indices. These measurements, in conjunction with other findings
from the history and physical examination, enable clinicians to stratify patients
based on risk and to determine the type of intervention. Educating patients
about proper foot care and periodic foot examinations are effective interventions
to prevent ulceration. Other possibly effective clinical interventions include
optimizing glycemic control, smoking cessation, intensive podiatric care,
debridement of calluses, and certain types of prophylactic foot surgery. The
value of various types of prescription footwear for ulcer prevention is not
clear.ConclusionsSubstantial evidence supports screening all patients with diabetes to
identify those at risk for foot ulceration. These patients might benefit from
certain prophylactic interventions, including patient education, prescription
footwear, intensive podiatric care, and evaluation for surgical interventions.

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Preventing Foot Ulcers in Patients With Diabetes

A cross-sectional multicentre study of randomly selected diabetic patients was performed using a standardised questionnaire and examination, to establish the prevalence of peripheral neuropathy in patients attending 118 hospital diabetes clinics in the UK. Vibration perception threshold was performed in two centres to compare with the clinical scoring systems. A total of 6487 diabetic patients were studied, 53.9% male, median age 59 years (range 18– 90 years), 37.4% Type 1 (insulin-dependent) diabetes mellitus, with a median duration of diabetes 8 years (0–62 years). The overall prevalence of neuropathy was 28.5% (27.4– 29.6 %) (95 % confidence interval) in this population. The prevalence in Type 1 diabetic patients was 22.7% (21.0– 24.4 %) and in Type 2 (non-insulin-dependent) diabetic patients it was 32.1 % (30.6–33.6 %). The prevalence of diabetic peripheral neuropathy increased with age, from 5% (3.1– 6.9 %) in the 20–29 year age group to 44.2 % (41.1–47.3 %) in the 70–79 year age group. Neuropathy was associated with duration of diabetes, and was present in 20.8 % (19.1–22.5 %) of patients with diabetes duration less than 5 years and in 36.8 % (34.9–38.7 %) of those with diabetes duration greater than 10 years. Mean vibration perception threshold measured at the great toe was 21.1±13.5 SD volts and correlated with the neuropathy disability score, r=0.8 p<0.001. In conclusion, diabetic peripheral neuropathy is a common complication associated with diabetes. It increases with both age and duration of diabetes, until it is present in more than 50% of Type 2 diabetic patients aged over 60 years. An increased awareness of the high prevalence of peripheral neuropathy, especially in older patients, should result in improved screening programmes in order to reduce the high incidence of neuropathic diabetic foot ulceration.

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A multicentre study of the prevalence of diabetic peripheral neuropathy in the United Kingdom hospital clinic population

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Growth Hormone Deficiency in Adulthood and the Effects of Growth Hormone Replacement: A Review

1. The metabolism of methylglyoxal by the glyoxalase system may be linked to the development of diabetic complications. The glyoxalase system was characterized in blood samples from patients with insulin-dependent diabetes mellitus (n = 43), patients with non-insulin-dependent diabetes mellitus (n = 107) and 21 normal healthy control subjects. 2. The concentrations of glyoxalase metabolites, methylglyoxal, S-D-lactoylglutathione and D-lactate, were increased in diabetic patients, relative to normal control subjects: methylglyoxal [median, range (n) pmol/g], insulin-dependent patients, 470.7, 85.6-1044.3 (42), P 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Glyoxalase system in clinical diabetes mellitus and correlation with diabetic complications.

Diagnosis of growth-hormone deficiency in adults

The effects of growth hormone (GH) deficiency in childhood are well recognized. These include shortness of stature with normal proportions, slow linear growth rate, delayed bone age with reduced bone density, excess adiposity with a predominantly truncal distribution, reduced lean tissue mass, and fasting hypoglycaemia (Collip et al., 1973; Hopwood et al., 1975; Tanner et al., 1977; Milner et al., 1979; Parra et al., 1979, Shore et al., 1980). These effects reflect the known metabolic actions of GH (Davidson, 1987; Press, 1988); GH promotes anabolism and lipolysis, and has complex actions on carbohydrate metabolism which can be summarized as insulinotrophic and insulin antagonistic. The effects of GH deficiency in adults have been appreciated only recently. There may be several reasons for this. Firstly, adults who developed panhypopituitarism from mass effects of a pituitary tumour or the treatment of the tumour survived, often returning to reasonably functional lives with conventional pituitary hormone replacement therapy. Secondly, GH treatment of such patients was not possible due to limited supplies of human pituitary-derived GH. The introduction of recombinant DNA technology has resulted in the production of authentic sequence human GH (rhGH) in potentially unlimited supplies, allowing treatment of conditions other than short stature. The aims of this review are to summarize the recent studies of GH treatment in adults with GH deficiency, thereby defining the syndrome of GH deficiency in adults, and to highlight areas for future investigation.

Peter H. Sönksen

Papers

A multicentre study of the prevalence of diabetic peripheral neuropathy in the United Kingdom hospital clinic population

Growth Hormone Deficiency in Adulthood and the Effects of Growth Hormone Replacement: A Review

Glyoxalase system in clinical diabetes mellitus and correlation with diabetic complications.

Diagnosis of growth-hormone deficiency in adults

The growth hormone deficiency syndrome in adults