LETTERSwas evidence of marked insulin deficiency Schizophrenia: Somatic Aspects. Lon-

don: Pergamon Press, 1957: 59.with a urinary C-peptide of 10.9 mg day−1LETTERS(mean of four tests), much lower than our 2. Mukherjee S, Schnur DB, Reddy R.non-diabetic range of 41 to 145 mg day−1. Family history of Type 2 diabetes in

schizophrenic patients. Lancet 1989;Islet cell antibodies were negative but heranti-insulin antibody levels were 35.7 % (8636): 495.

Diabetes Mellitus Associated with Mito- (normal ,10 %). Urinary protein was less 3. Spector TD, Silman AJ. Rheumatoidchondrial Myopathy and Schizophrenia: than 0.1 g day−1, urine albumin excretion arthritis, diabetes and schizophrenia.a Possible Link Between Diabetes Mellitus 17.6 mg day−1 with a normal creatinine Lancet 1990; 335 (8683): 228–229.and Schizophrenia clearance (1.38 ml s−1, normal range 1.16 4. Finney GO. Juvenile-onset diabetes

and schizophrenia? Lancet 1989; 2to 1.34 ml s−1).Schizophrenia is associated with impaired Electromyography (EMG) showed (9673): 1214–1215.glucose tolerance1 and 18 to 19 per cent myopathic changes in the sternocleido- 5. Suzuki T, Koizumi J, Shiraishi H,of patients with schizophrenia have a mastoid muscles. Ragged red fibres were Ofuku K, Sasaki M, Hori T, Ohkoshifamily history of non-insulin-dependent observed on muscle biopsy. Other investi- N. Psychiatric disturbance in mito-(Type 2) diabetes mellitus (NIDDM).2 gations included an EEG, which showed chondrial encephalomyopathy. JAutoimmune insulin-dependent (Type 1) slow wave activity. On the basis of the Neurol Neurosurg Psychiatry 1989;diabetes mellitus (IDDM), however, has EMG and muscle biopsy, she was diagnosed 52: 920–922.been reported to have a negative associ- as having mitochondrial myopathy. 6. Odawara M, Sasaki K, Yamashita K.ation with schizophrenia.3,4 Mitochondria During her hospitalization, her diabetes Prevalence and clinical characteriz-play an important role in cerebral function regimen was converted from intermediate ation of Japanese diabetes mellitusthrough the production of ATP and mito- to mixed insulins. She did not achieve with an A-to-G mutation at nucleotidechondrial dysfunction may lead to psychi- good glycaemic control, despite 18 to 26 3243 of the mitochondrialatric disorders.5 Mitochondrial dysfunc- units of insulin. Apart from this, she was tRNALeu(UUR) gene. J Clin Endocrinoltion also contributes to the pathogenesis also hyponatraemic on admission and Metab 1995; 80: 1290–1294.of about 1 % of NIDDM,6 but rarely was diagnosed as having psychogenic 7. Odawara M, Sasaki K, Nagafuchi S,to autoimmune IDDM or autoimmune polydipsia after a normal response to Tanae A, Yamashita K. Lack of associ-thyroid diseases.7 We experienced a case water deprivation. Water restriction suc- ation between mitochondrial geneof mitochondrial myopathy associated cessfully increased serum sodium to mutation np 3243 and Type 1 diabeteswith NIDDM, as well as maternally 141 mmol l−1. mellitus and autoimmune thyroid dis-inherited schizophrenia. The present rare Our patient had insulin-requiring Type eases. Lancet 1994; 344: 1086.case suggests an involvement of mitochon- 2 diabetes mellitus (NIDDM), associateddrial dysfunction in the pathogenesis of with an atypical MELAS syndromeschizophrenia as well as of diabetes (mitochondrial encephalomyopathy, lac-mellitus, which have been shown to be tic acidosis and stroke-like episodes) and Insulin Therapy and Risk of Retinopathyassociated with each other by epidemio- schizophrenia. We considered the possi- in Type 2 Diabetes Mellituslogical studies. bility of a common mechanism linking

A 52-year-old female was admitted to the three diseases. An A-to-G mutation atour hospital because of systemic muscle There are worrying uncertainties sur-np 32436 of the mitochondrial gene haswasting and decreased muscle power. Past rounding the conclusions of Henricssonbeen implicated in the development ofhistory included diabetes mellitus, diag- et al.1 when they tackle the difficultNIDDM and mitochondrial myopathiesnosed when she was 21 and treated with problem of dissecting the influence ofand has been associated with schizo-insulin since age 22. At the age of 23, hyperglycaemia on the worsening ofphrenia in epidemiological studies. Ourshe had developed delusional mood and retinopathy from that of the initiation ofcase is compatible with the hypothesisdelusions of reference and was diagnosed insulin treatment in non-insulin-depen-that a subtype of schizophrenia, NIDDMas having schizophrenia, confirmed by the dent diabetic patients. When they correctand mitochondrial myopathy may all havecriteria of DSM-IIIR. There was a maternal for HbA1c the relative risk of introductionbeen caused by mitochondrial dysfunc-family history of schizophrenia, in the of insulin treatment for progression oftion. Schizophrenia is a heterogeneousmother and uncle. She was treated with retinopathy by more than three levels,disorder like NIDDM and it is not knownmajor tranquillizers and sedatives but had apparently at any time in the study, thewhether mitochondrial dysfunction con-experienced recurrent exacerbations of HbA1c values seem to be those for thetributes to the pathogenesis of most cases.schizophrenic symptoms. Aged 31, she whole study period, though I’m unsure ifFurther studies are necessary, but our casedeveloped dementia which progressed the individual, ranked HbA1c values aresuggests that an association of diabetesgradually. She had occasional episodes of used or whether ‘below the median ormellitus with schizophrenia may be partlyloss of consciousness. The muscle weakness not’ is being entered.due to mitochondrial dysfunction causedwith which she presented to our hospital The authors are interested in theby mitochondrial gene abnormalities.was of recent onset. increased risk or irreversible progression

of retinopathy after insulin therapy, as wellOn admission, her height was 159 cm, M. Odawaraa, M. Isakaa, K. Tadaa, H.her body weight 39.1 kg, with a body as their confirmation of the relationshipMizusawab, K. Yamashitaa

mass index of 15.5 kg m2 −1. She was between hyperglycaemia and retinopathyaDepartment of Endocrinology and Metab-emaciated. She was found to be alert but progression in non-insulin-dependent dia-olism, University of Tsukuba, Japanhad impaired memory, bilateral senso- betic patients; incidentally, the two pre-bDepartment of Neurology, Tokyo Medi-roneural hearing loss and moderately vious references they quote on this bothcal and Dental University, Japandecreased muscle power on manual test- have at least one forerunner2 whose

Figure 2, though far from directly compa-ing. Her sternocleidomastoid muscleswere wasted. There was no evidence of rable, is reminiscent of the present

Figure 1. So one might postulate bothperipheral neuropathy but she did have Referencesbackground diabetic retinopathy. high HbA1c levels before the start of

therapy and relatively low ones after it toOn admission, her HbAlc was 8.2 % 1. A. Richter D. Biochemical aspectsof schizophrenia. In: Richter D, ed.(non-diabetic range 4.9 to 6.5 %) and there be injurious (or perhaps the individual

503CCC 0742–3071/97/060503–02$17.50 1997 by John Wiley & Sons, Ltd. DIABETIC MEDICINE, 1997; 14: 503–504

LETTERSchange from before to after—or the drop 2. Howard-Williams J, Hillson RM, Bron the critical change resulting in the emerg-

ence of what they termed the ‘non-thriftyin the first x months—is what is important). A, Asdry P, Mann JI, Hockaday TDR.Retinopathy is associated with higherIn the calculation referred to above, genotype’. Europeans are different from

the rest of the world in not having thetherefore, they are muddling (and so glycaemia in maturity-onset-type dia-betes. Diabetologia 1984; 27: 198–202.possibly diminishing) the glycaemic thrifty genotype but also by being able to

digest lactose throughout their lifetime,influences. For instance, if hypergly-caemia before introduction of insulin is rather than the usual mammalian pattern

of lactase decline in the post-weaningparticularly important, this effect will have The Thrifty Genotype Hypothesisbeen diminished irregularly by mixing it period. A high rate of lactose absorption

Swinburn concluded his review of thewith the lower values that followed use in a population is also evidence of a longthrifty genotype hypothesis1 by askingof insulin, so possibly exaggerating in any history of dairying. In Europeans thisan important question about Europeans:multivariate analysis the influence of the began with the influx of Indo-Europeans‘Why does this ethnic group have suchtherapy change per se. Indeed, when pre- some 6–7000 years ago and representedan unusually low rate of NIDDM?’ Twoinsulin HbA1c levels alone are used (as one aspect of the secondary productsrecent publications have addressed thisabove or below the median and inevitably revolution associated with the develop-question and have independentlyjust for those converted to insulin), they, ment of agriculture. In studies of popu-advanced similar hypotheses in proposingand presumably not the post-insulin lev- lations with data on both lactose tolerancean essential role for a change in dietaryels, are related to progression of retino- and diabetes there is an absence ofcarbohydrate in Europeans as the factorpathy. Hence, to be convinced of the populations exhibiting both high lactosewhich relaxed the selection pressure forimportance for retinopathy of the risk of absorption rates and high diabetes rates.4maintaining a thrifty gene(s).2,3conversion to insulin, should not the pre- The availability of glucose through lactose

It is generally considered that the thriftyinsulin HbA1c levels alone be used in the ingestion and absorption would also pro-gene(s) determines or is associated withmultivariate analysis of the whole group? vide the constant supply of glucose whichinsulin resistance and that it provided our(Also if one is worried about a temporal would make the need for insulin resist-ancestors with survival advantages inshift in overall glycaemic control, the ance unnecessary.times of fluctuating and uncertain foodvalues for the non-insulin-treated could The observation that certain populationsavailability. The reason for the emergencebe those in the first half of their time in such as the Pima Indians and the Nauruansof a thrifty/insulin resistance genotypethe study (or whatever would be the have a very high prevalence of diabetesremains speculative. Brand Miller andcorrect comparable time), or before a can be explained by pressures promotingColagiuri have postulated a critical evol-certain date, or whatever?) the survival of individuals with the thriftyutionary role for the carnivorous dietWhen the risk of blindness or lesser genotype. Events which could haveof our ancestors which contained littlevisual impairment associated with intro- resulted in such genetic bottlenecks areavailable carbohydrate and the advantageduction of insulin is given, no correction well documented in these populations.2which insulin resistance would have pro-is given for either glycaemic level or Changes in available carbohydrate,vided in maintaining plasma glucose forretinopathy at entry. either as a general increase or in a specificessential organs especially during periodsAlso it would seem important that the component such as lactose, represent aof starvation and during reproduction.2ocular changes occurring only after the plausible explanation for the emergence

Since the thrifty genotype appears tointroduction of insulin should be exam- of the ‘non-thrifty genotype’.have been universal among our ancestors,ined in regard to that therapy change.what selection pressures relaxed the needIf it is wished to examine the effect of a S. Colagiuria, J.S. Allenb, J.C. Brand Mil-for this genotype in Europeans? Changesdownward step in glycaemic control (as lerc, S.M. Cheerb

in gene frequency usually require 5–opposed to the early days of exogenous aDepartment of Endocrinology, Prince of10 000 years to manifest and thereforeinsulin—the paper finds no harm in long- Wales Hospital, High St, Randwick, NSWthe answer is to be found in the periodterm insulin use), why was the change from 2031, Australiasince the last Ice Age which ended aboutmanagement by dietary advice alone to bDepartment of Anthropology, University10 000 years ago. As the thrifty gene isoral hypoglycaemic agents not examined? of Auckland, Private Bag 92019, Auck-postulated to have developed to promoteWhile too rapid substantial reductions land, New Zealandsurvival in an uncertain food environment,in glycaemic level may well be more cHuman Nutrition Unit, Department ofit is probable that relaxation of dietaryharmful to certain types of retinopathy, it Biochemistry G08, University of Sydney,pressures were responsible for the geno-will take a lot more information from NSW 2006, Australiatypic change. The most significant changethese authors to convince me of thein the nutritional environment operatinghazard, even in the short term, of prescrip-after the last Ice Age was a change intion of an agent likely, if introducedavailable carbohydrate. Increasing avail-at the appropriate time, to bring some Referencesable carbohydrate would obviate the needsubstantial benefits to non-insulin-depen-for insulin resistance to maintain a steadydent patients.supply of glucose for vital organs. 1. Swinburn BA. The Thrifty Genotype

Derek Hockaday The advent of agriculture has been pro- Hypothesis: how does it look afterEast Hanney, Wantage, Oxfordshire posed as the specific historical event 30 years? Diabetic Med 1996; 13:OX12 0JF resulting in an increased intake of available 695–699.

2. Brand Miller J, Colagiuri S. The carni-carbohydrate.2 Since Europeans wereamong the first to adopt agriculture, the vore connection: dietary carbo-

hydrate in the evolution of NIDDM.selection pressure for insulin resistanceReferenceswould have been relaxed much sooner in Diabetologia 1994; 37: 1280–1286.

3. Allen JS, Cheer SM. ‘Civilisation’ and1. Henricsson M, Nilsson A, Janzon L, our European ancestors, thereby relaxingthe necessity for the thrifty genotype.Groop L. The effect of glycaemic the thrifty genotype. Asia Pacific J

Clin Nutr 1996; 4: 341–342.control and the introduction of insulin It is however possible that a specificcarbohydrate component was the desel-therapy on retinopathy in non-insulin- 4. Allen JS, Cheer SM. The non-thrifty

genotype. Current Anthropologydependent diabetes mellitus. Diabetic ecting influence. Allen and Cheer3,4 postu-late an increase in lactose ingestion asMed 1997; 14: 123–131. 1996; 37: 831–842.

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