DIABETES

1922 Banting FG, Best CH. Internal secretion of the pancreas. J Lab Clin Med 1922; VII: 251-266.

The work reported in this classic paper eventually led to a Nobel Prize in 1923 for Banting and Macleod, in whose Toronto laboratory the work was done. Frederick Banting (1891-1941) (figure 11) was a Canadian orthopaedic surgeon who became an assistant in physiology in Ontario where he worked in Richard McLeod’s laboratory with Charles Best, a medical student. It was here, after many ups and downs and arguments and with the help of Bertram Collip, a highly trained biochemist, to extract the insulin, that they eventually produced and tried the insulin on a diabetic patient in 1922.
The paper begins –“The hypothesis underlying this series of experiments was first formulated by one of us in November 1920 (Banting was then assistant in Physiology at Western University, London, Ontario) while reading an article dealing with the relation of the isles of Langerhans to diabetes (Barron M: The relation of the islets of Langerhans to diabetes with special reference to cases of pancreatic lithiasis. Surg Gynec Obstetr 1920; xxxi :437-448). From the passage in the article which gives a resume of degenerative changes in the acini of the pancreas following ligation of the ducts, the idea presented itself that since the acinous but not the island tissue degenerates after this operation, advantage might be taken of this fact to prepare an active extract of the islet tissue. The subsidiary hypothesis was that trypsinogen or its derivatives was antagonistic to the internal secretion of the gland. The failures of other investigators in this much worked field were thus accounted for”.
The authors concluded from their experiments that –“intravenous injections of extract from dog’s pancreas, removed from 7 to 10 weeks after ligation of the ducts, invariably exercises a reducing influence upon the percentage sugar of the blood and the amount of sugar excreted in the urine”

This medical classic is a “good read” and one of the most significant medical papers of the 20th century as also is Moses Barron's paper that gave him the idea (above). It is included here not only for its historical interest but also for its relevance to CF as the majority of those affected will eventually develop CF related diabetes in adult life. Although the Islets of Langerhans in CF are functioning adequately through childhood in most patients, despite their severe exocrine pancreatic insufficiency, they are eventually destroyed resulting in the majority of adults with CF developing diabetes mellitus. Efforts to prevent the slow destruction of the pancreas and prevent or delay the onset of CF related diabetes will surely become an area of research as more people survive to develop this complication which has an adverse effect both on their prognosis and quality of life.

1955 Shwachman H, Leubner H. Mucoviscidosis. Advan Pediat 1955; 7:249-323. [PubMed]
The paper contains the first detailed report of symptomatic diabetes mellitus and CF in a white boy aged 5 years from Kaloa, Hawaii – considered to be the superimposition of one serious disease on another. The authors note that “mucoviscidosis is so well established today that we seldom see individual case reports except in areas where interest in the disease is awakening (for example South Africa, Canada and Germany). Rather we look forward to monographs such as Bodian’s (1952 above) and May’s (May CD. Cystic fibrosis of the pancreas in infants and children. Springfield Ill: Charles C Thomas. Publisher, 1954 above) where accumulated experience is recorded”.
They note that in Bodian’s book Cedric Carter, the geneticist, combined the data from Andersen and Hodges, Lowe, May and Reed with his own to confirm the expected probability of 1 in 4 children being affected. The importance of di Sant’Agnese’s recent (1953) description of the sweat electrolyte abnormality is mentioned particularly its importance in the recognition of the 5 - 10% of people with CF without clinical pancreatic insufficiency – but the tryptic activity of duodenal juice was still of great importance in diagnosis. Shwachman describes their experience of inducing sweating in 300 children by placing the child in a plastic suit bag for 30-90 minutes with pieces of covered gauze on the back. Values of over 80 meq/l were considered diagnostic of cystic fibrosis.
The beneficial effect of controlling infection with antibiotics in contrast to the relatively unsuccessful attempts with various inhalations including trypsin and oral iodides was stressed – “early recognition of the disease and prompt antibiotic therapy may be so encouraging that parents as well as doctor begin to question the original diagnosis”!
Finally, Shwachman notes that the average age of death from 1940-48 was 12.8 months and from 1949-53 was 45.2 months – the broad spectrum antibiotics came into use in 1949 and were considered likely to be one of the reasons for the improvement.
This 74 page paper, with 142 references, is a very detailed review of the current knowledge of CF up to that time by Harry Shwachman, written with the assistance of Hugo Leubner of the WHO and Pincus Catzel, then a research fellow; it makes very interesting reading.

1961 Huhnstock K, Schwarz G. On mucoviscidosis in adults and diabetes mellitus. Klinische Wochenschrift 1961; 39:854-7. [PubMed]
These authors screened 250 adults with diabetes mellitus using Shwachman plates (Shwachman et al, 1956 above) and those who were positive had sweat tests performed by the bag method. Nine of the 250 diabetic adults had positive sweat tests but no other signs of cystic fibrosis.
These findings are difficult to explain as diabetes mellitus is usually a late feature in the progression of cystic fibrosis. Also the ages of the patients (between 49 and 66 years) were quite against their having cystic fibrosis. It is difficult to accept these findings particularly as there were no other signs of cystic fibrosis in these middle aged patients. Also a number of authors had found some apparently healthy adults with sweat tests with values of sodium and chloride over 60 meq/l. This paper was followed by a number of publications on the relationship between established diabetics and cystic fibrosis. The first description of diabetes mellitus in cystic fibrosis is usually attributed to Shwachman & Leubner, 1955 (above)..

1962 Rosan RC, Shwachman H, Kulczycki LI. Diabetes mellitus and cystic fibrosis of the pancreas. Laboratory and clinical observations. Am J Dis Child 1962; 104:625-34. [PubMed]
One of the early descriptions of diabetes mellitus in cystic fibrosis; the first was in 1955 in an article by Shwachman & Leubner (above). In the present paper 10 patients with diabetes mellitus were identified in a CF population of about 1300 patients seen since 1947 - one adult, three teenagers and the rest children. Reviewing the 10 patients – eight required insulin therapy, they noted that diabetes complicates management but does not necessarily shorten survival; it may begin at any age; four of the 10 patients were mentally retarded – an unusual occurrence in CF which was not discussed; the complication was indistinguishable from juvenile diabetes except ketosis was very rare; all were completely pancreatic insufficient. The authors predicted that subclinical diabetes must exist in a large proportion of people with CF. This prophetic observation was absolutely correct but was a new concept at the time when there were very few adults with cystic fibrosis. There were so few patients with diabetes mellitus and CF that this paper reporting 10 patients was published.

1969 Milner AD. Blood glucose and serum insulin levels in children with cystic fibrosis. Arch Dis Child 1969; 44:351-355. [PubMed]
One of the early studies on glucose metabolism from Great Ormond Street, London by Tony Milner at a time when few patients survived to an age when they developed diabetes. However, it had been predicted that this might occur as patients became older. Glucose and insulin levels were measured after oral glucose and intravenous glucose, glucagon and tolbutamide in 61 children with CF. The results suggested that the increased incidence of impaired glucose tolerance was due to a defect in the release of an glucagon-like substance from the alimentary system in addition to defective islet cell function. (also Rosan et al, 1962 above; Huhnstock K & Schwarz G, 1961 above)

1992 Lanng S, Thorsteisson B, Nerup J, Koch C. Influence of the development of diabetes mellitus on the clinical status in patients with cystic fibrosis. Eur J Paediatr 1992; 151:684-687. [PubMed]
The first of a series of papers about CF related diabetes (CFRD) from Copenhagen and other centres. The new and important message from this paper being that diabetes mellitus adversely affects progress for some time before it becomes clinically obvious. When diabetes develops in CF patients, an insidious decline in overall clinical status is observed for some years prior to its clinical diagnosis. Whether clinical deterioration in CF leads to DM, or pre-diabetes results in declining CF clinical status is unclear. Accumulating evidence suggests that the latter may be the case since insulin therapy seems to improve lung function in cystic fibrosis.
The subject is reviewed in detail in the CF Trust’s consensus document “Management of Cystic Fibrosis related Diabetes Mellitus. June 2004 - the full text of which is on the CF Trust website www.cftrust.org.uk.
This Danish study encouraged the introduction of the policy of searching for glucose intolerance when patients of 12 years and older were seen for their Annual Review - a policy agreed by most, but not all, CF physicians.

2000 Moran A. Cystic fibrosis-related diabetes: an approach to diagnosis and management. [PubMed]
The Cystic Fibrosis Foundation held a consensus conference in 1998 to define the current standards for the diagnosis and care of CF related diabetes (Moran A, Hardin D, Rodman D et al. Diagnosis, screening, and management of CFRD: a consensus conference report. J Diabetes Res Clin Pract 1999: 45: 61-73). This article reviews those recommendations, and presents the practical approach to the management of CFRD used at the University of Minnesota.
The CF Foundation recommendations were recently reviewed again (Moran A. Updates on CFRD guidelines. Pediatr Pulmonol 2009; Suppl 32:208-209. S19.4). There was a further CFF Consensus Conference on CFRD in Sept. 2009.

Dr Antoinette Moran (figure 13) was awarded the CF Foundation's Distinguished Clinical Achievement Award in 2007 for her work in this area.

The UK CF Trust consensus document Management of Cystic Fibrosis Related Diabetes Mellitus by the CF Trustss Diabetes Working Group was published in 2004 and is available on the website (www.cftrust.org.uk). Diabetes mellitus is one of the major age-related complications which is likely to affect all adults with CF eventually.

Starkman H. Das S. Cystic fibrosis presenting as new onset diabetes mellitus in adolescent twins. Pediatr Diabet 2004; 5:99-101. [PubMed]Identical adolescent twin girls presented with symptoms consistent with type 1 diabetes. Medical work up for evaluation of gastrointestinal symptoms led to a diagnosis of cystic fibrosis (CF) in both. These cases suggest that diabetes can be a presenting symptom of CF in the absence of pulmonary symptomatology.

This is the first report of such a presentation of CF. In 1961 Huhnstock K, Schwarz G reporting on mucoviscidosis in adults and diabetes mellitus [PubMed] (above) screened 250 adults with diabetes mellitus using Shwachman plates and those who were positive had sweat tests performed by the bag method. Nine of the 250 diabetic adults had positive sweat tests but no other signs of cystic fibrosis. It seems most unlikely that they had CF.

2006 Andersen HU, Lanng S, Pressler T, Laugesen CS, Mathiesen ER. Cystic fibrosis-related diabetes: the presence of microvascular diabetes complications. Diabetes Care 2006; 29:2660-3. [PubMed]
Thirty-eight patients aged 30 years (range 18-55yrs) with CF-related diabetes for 20 years (0-31yrs) were screened for diabetes complications at the Copenhagen CF Centre. Because of chronic pulmonary infections, the majority of patients were regularly treated with aminoglycoside and cyclosporine was given to those who had lung transplants. Since the pharmacological treatment of lung transplant patients could influence metabolic regulation and renal function, the results were given separately for nontransplanted (n = 29) and transplanted (n = 9) CF patients.
Nine of these diabetic patients (27%) had retinopathy, two of whom had proliferative retinopathy requiring laser treatment. Lung transplantation did not affect the prevalence of retinopathy. In 29 non-transplanted patients, nine had hypertension, three microalbuminuria, and one elevated creatinine; none had macroalbuminuria. In transplanted patients (9), eight had hypertension, two had microalbuminuria, and none had macroalbuminuria; seven of the nine had elevated plasma creatinine, and severely reduced glomerular filtration rate was significantly more frequent.

So a high frequency of diabetic retinopathy was found in patients with insulin-treated CF-related diabetes, stressing the need for a regular screening program as in type 1 diabetes. Severely impaired kidney function was common in lung transplant patients, probably secondary to cyclosporine treatment but many would also have had life long regular courses of intravenous aminoglycosides. As age increases so do complications. Eventually the majority of older people with CF will develop diabetes and it is clear that eventually many will develop diabetic complications particularly retinopathy. The added complications associated with immunosuppressant drugs in those who have had lung transplants and the effects of repeated courses of aminoglycosides contribute to the high frequency of renal complications.

2007 Schwarzenberg SJ, Thomas W, Olsen TW, Grover T, Walk D, Milla C, Moran A. Microvascular complications in cystic fibrosis-related diabetes. Diabetes Care 2007; 30:1056-1061. [PubMed]
The incidence of cystic fibrosis-related diabetes (CFRD) and the prevalence of diabetic microvascular complications were determined at the University of Minnesota. During 1990-2005, 775 patients aged 6 years and older were followed. CFRD was diagnosed in 285 subjects (52% female), 64% of whom had fasting hyperglycaemia. No subject with CFRD without fasting hyperglycaemia had retinopathy or abnormal urine albumin/creatinine ratio. In CFRD subjects with fasting hyperglycaemia and diabetes for 10 years or longer, 14% had microalbuminuria and 16% had retinopathy. Autonomic neuropathy and gastrointestinal symptoms each were seen in 52% and somatic abnormalities in 22% of patients with or without fasting hyperglycaemia.
The authors concluded that diabetic microvascular complications occur in CFRD, although the prevalence of retinopathy and nephropathy appears to be less than that found in other forms of diabetes. They advised that annual complication screening should occur after known diabetes duration of 5 years in patients with CFRD with fasting hyperglycaemia.

It is likely that CFRD will prove to be an increasingly important complication as the age of the adult CF population increases as will its complications as described here (Also Andersen et al, 2006 above).

2007 Battezzati A, Battezzati PM, Costantini D, Seia M, Zazzeron L, Russo MC, Dacco V, Bertoli S, Crosignani A, Colombo C. Spontaneous hypoglycaemia in patients with cystic fibrosis. Euro J Endocrinol 2007; 156:369-376. [PubMed]
A total of 129 CF patients without stable diabetes received 188 oral glucose tolerance tests. Fasting plasma glucose of < 60 mg/dl (3.3 mmo/l) was detected in 14% of studies and reactive hypoglycaemia (PG < 50 mg/dl (2.8 mmo/l)) in 15%. The oral glucose tolerance test-based diabetes frequency was similar in the lowest quartile (Q1) and Q2-3 for fasting plasma glucose (10 and 8%), with higher glucose increment and area under the curve in Q1. Insulin and C-peptide levels were similar among fasting plasma glucose (FPG) quartiles. Those with class I CFTR mutations had higher insulin concentrations than class II, especially in Q1 for FPG. Lower FPG was associated with more frequent hospitalization rates and lower Shwachman scores.

Fasting asymptomatic hypoglycaemia is frequent and possibly related to inappropriate insulin secretion control in class I mutation carriers. Low fasting plasma glucose does not exclude impaired glucose tolerance and diabetes in CF and does reflect worse clinical status.

2008 van den Berg JM. Morton AM. Kok SW. Pijl H. Conway SP. Heijerman HG. Microvascular complications in patients with cystic fibrosis-related diabetes (CFRD). J Cyst Fibros 2008; 7:515-519. [PubMed]
79 patients with CFRD were matched with 79 patients with DM1 according to sex, age and duration of insulin therapy. Retinopathy, peripheral neuropathy, nephropathy and microalbuminuria were the microvascular complications assessed. Risk factors studied were: smoking, BMI, HbA1c, cholesterol, cholesterol/HDL ratio, diastolic and systolic blood pressure. Both groups had the same number of microvascular complications (29%). CFRD patients showed more microalbuminuria (21% versus 4.1%; p=0.003), while retinopathy was more common in patients with DM1 (24% versus 10%; p=0.044). The prevalences of peripheral neuropathy and nephropathy were similar. Patients with CFRD had lower BMI (p<0.0001), total cholesterol (p<0.0001) and HbA1c (p=0.056) levels, and a lower prevalence of smokers (p<0.0001). Cholesterol/HDL ratio and diastolic and systolic blood pressure were similar in both groups. The microvascular complications shown by patients with CFRD are similar to those seen in patients with DM1 but with a lower prevalence of retinopathy and a higher prevalence of microalbuminuria. The latter may reflect the influence of other cystic fibrosis-related factors on renal function.

2009 Moran A. Dunitz J. Nathan B. Saeed A. Holme B. Thomas W. Cystic fibrosis-related diabetes: current trends in prevalence, incidence, and mortality. Diabetes Care 2009; 32:1626-1631. [PubMed]
Cystic fibrosis (CF)-related diabetes (CFRD) diagnosis and management have considerably changed since diabetes was first shown to be associated with a poor prognosis in subjects with CF. Current trends in CFRD prevalence, incidence, and mortality were determined from a comprehensive clinical database. Data were reviewed from 872 CF patients followed at the University of Minnesota during three consecutive intervals: 1992-1997, 1998-2002, and 2003-2008. CFRD is currently present in 2% of children, 19% of adolescents, and 40-50% of adults. Incidence and prevalence are higher in female subjects aged 30-39 years; otherwise, there are no sex differences. In younger individuals, CFRD without fasting hyperglycemia predominates, but fasting hyperglycemia prevalence rises with age. CFRD mortality has significantly decreased over time. From 1992-1997 to 2003-2008, mortality rate in female subjects dropped by >50% from 6.9 to 3.2 deaths per 100 patient-years and in male subjects from 6.5 to 3.8 deaths per 100 patient-years. There is no longer a sex difference in mortality. Diabetes was previously diagnosed as a perimorbid event in nearly 20% of patients, but of 61 patients diagnosed with diabetes during 2003-2008, only 2 died. Lung function but not nutritional status is still worse in CF patients with diabetes compared with those without diabetes. Nutritional status and pulmonary status are similar between patients without fasting hyperglycemia and those with fasting hyperglycemia.

CONCLUSIONS: Previously noted sex differences in mortality have disappeared, and the gap in mortality between CF patients with and without diabetes has considerably narrowed. We believe that early diagnosis and aggressive treatment have played a major role in improving survival in these patients.

A useful review of changes in the feat rues of CFRD by Antoinette Moran an expert on CFRD from Minnesota

2009 Moran A. Pekow P. Grover P. Zorn M. Slovis B. Pilewski J. Tullis E. Liou TG. Allen H. Cystic Fibrosis Related Diabetes Therapy Study Group. Insulin therapy to improve BMI in cystic fibrosis-related diabetes without fasting hyperglycemia: results of the cystic fibrosis related diabetes therapy trial. Diabetes Care 2009; 32:1783-1788. [PubMed]
Cystic fibrosis-related diabetes (CFRD) without fasting hyperglycemia (CFRD FH-) is not associated with microvascular or macrovascular complications, leading to controversy about the need for treatment. The Cystic Fibrosis Related Diabetes Therapy (CFRDT) Trial sought to determine whether diabetes therapy improves BMI in these patients. A three-arm multicenter randomized trial compared 1 year of therapy with premeal insulin as part, repaglinide, or oral placebo in subjects with cystic fibrosis who had abnormal glucose tolerance. One hundred adult patients were enrolled. Eighty-one completed the study, including 61 with CFRD FH- and 20 with severely impaired glucose tolerance (IGT). During the year before therapy, BMI declined in all groups. Among the group with CFRD FH-, insulin-treated patients lost 0.30 +/- 0.21 BMI units the year before therapy. After 1 year of insulin therapy, this pattern reversed, and they gained 0.39 +/- 21 BMI units (P = 0.02). No significant change in the rate of BMI decline was seen in placebo-treated patients (P = 0.45). Repaglinide-treated patients had an initial significant BMI gain (0.53 +/- 0.19 BMI units, P = 0.01), but this effect was not sustained. After 6 months of therapy they lost weight so that by 12 months there was no difference in the rate of BMI change during the study year compared with the year before (P = 0.33). Among patients with IGT, neither insulin nor repaglinide affected the rate of BMI decline. No significant differences were seen in the rate of lung function decline or the number of hospitalizations in any group. CONCLUSIONS: Insulin therapy safely reversed chronic weight loss in patients with CFRD FH-.

A conclusive result showing that insulin improves the nutritional state of people with CF who have impaired glucose tolerance without fasting hyperglycaemia.

Two more recent reviews not included in main text are as follows -

2010 Stecenko AA, Moran A. Update on cystic fibrosis-related diabetes. Curr Opin Pulm Med 2010; 16:611-615. [PubMed]
A detailed review of recent publications on cystic fibrosis-related diabetes (CFRD) with a particular focus on the interplay between cystic fibrosis (CF) lung disease and diabetes.

2010 Laguna TA, Nathan BM, Moran A. Managing diabetes in cystic fibrosis. Diabetes Obes Metab 2010; 12:858-64. [PubMed]
Cystic fibrosis related diabetes (CFRD) is the most common co-morbidity in persons with cystic fibrosis (CF). As the life expectancy of persons with CF continues to increase, the need to proactively diagnose and aggressively treat CFRD and its potential complications has become more apparent. CFRD negatively impacts lung function, growth and mortality, making its diagnosis and management crucial in a population already at high risk for early mortality. Compared to type 1 and type 2 diabetes, CFRD is a unique entity, requiring a thorough understanding of its unique pathophysiology to facilitate the creation and utilization of an effective medical treatment plan. The physiology of CFRD is complex, likely consisting of a combination of insulin deficiency, insulin resistance and a genetic predisposition towards the development of diabetes. However, the hallmark of CFRD is insulin deficiency, necessitating the use of exogenous insulin as the mainstay of therapy. Insulin administration, in combination with a multidisciplinary team of health professionals with expertise in the care of patients with CF and CFRD, is the cornerstone of the care for these patients. The goals of treatment of the CFRD population are to reverse protein catabolism, maintain a healthy weight, and reduce acute and chronic diabetes complications. Creating a partnership between the treatment team and the patient is the ideal way to accomplish these goals and is essential for successful diabetes care.